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Open AccessReview Adipokines and Non-Alcoholic Fatty Liver Disease: Multiple Interactions

by Timon E. Adolph, Christoph Grander, Felix Grabherr and Herbert Tilg

Int. J. Mol. Sci. 2017, 18(8), 1649; doi:10.3390/ijms18081649

Received: 18 July 2017 / Revised: 18 July 2017 / Accepted: 26 July 2017 / Published: 29 July 2017

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Abstract

Accumulating evidence links obesity with low-grade inflammation which may originate from adipose tissue that secretes a plethora of pro- and anti-inflammatory cytokines termed adipokines. Adiponectin and leptin have evolved as crucial signals in many obesity-related pathologies including non-alcoholic fatty liver disease (NAFLD). Whereas

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Accumulating evidence links obesity with low-grade inflammation which may originate from adipose tissue that secretes a plethora of pro- and anti-inflammatory cytokines termed adipokines. Adiponectin and leptin have evolved as crucial signals in many obesity-related pathologies including non-alcoholic fatty liver disease (NAFLD). Whereas adiponectin deficiency might be critically involved in the pro-inflammatory state associated with obesity and related disorders, overproduction of leptin, a rather pro-inflammatory mediator, is considered of equal relevance. An imbalanced adipokine profile in obesity consecutively contributes to metabolic inflammation in NAFLD, which is associated with a substantial risk for developing hepatocellular carcinoma (HCC) also in the non-cirrhotic stage of disease. Both adiponectin and leptin have been related to liver tumorigenesis especially in preclinical models. This review covers recent advances in our understanding of some adipokines in NAFLD and associated HCC. Full article

(This article belongs to the Special Issue Adipokines)

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Open AccessReview Dietary Composition Independent of Weight Loss in the Management of Non-Alcoholic Fatty Liver Disease

by Tannaz Eslamparast, Puneeta Tandon and Maitreyi Raman

Nutrients 2017, 9(8), 800; doi:10.3390/nu9080800

Received: 23 June 2017 / Revised: 18 July 2017 / Accepted: 21 July 2017 / Published: 26 July 2017

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Abstract

Poor dietary composition is an important factor in the progression of non-alcoholic fatty liver disease (NAFLD). The majority of NAFLD patients follow diets with overconsumption of simple carbohydrates, total and saturated fat, with reduced intake of dietary fiber and omega-3 rich foods. Although

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Poor dietary composition is an important factor in the progression of non-alcoholic fatty liver disease (NAFLD). The majority of NAFLD patients follow diets with overconsumption of simple carbohydrates, total and saturated fat, with reduced intake of dietary fiber and omega-3 rich foods. Although lifestyle modifications including weight loss and exercise remain the keystone of NAFLD management, modifying dietary composition with or without a calorie-restricted diet may also be a feasible and sustainable strategy for NAFLD treatment. In the present review article, we highlight the potential therapeutic role of a “high quality healthy diet” to improve hepatic steatosis and metabolic dysfunction in patients with NAFLD, independent of caloric restriction and weight loss. We provide a literature review evaluating the evidence behind dietary components including fiber-, meat- and omega-3-rich diets and, pending further evidence, we concur with the EASL-EASD-EASO Clinical Guidelines recommendation of the Mediterranean diet as the diet of choice in these patients. Full article

(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)

Open AccessArticle The Combined Intervention with Germinated Vigna radiata and Aerobic Interval Training Protocol Is an Effective Strategy for the Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD) and Other Alterations Related to the Metabolic Syndrome in Zucker Rats

by Garyfallia Kapravelou, Rosario Martínez, Elena Nebot, María López-Jurado, Pilar Aranda, Francisco Arrebola, Samuel Cantarero, Milagros Galisteo and Jesus M. Porres

Nutrients 2017, 9(7), 774; doi:10.3390/nu9070774

Received: 24 April 2017 / Revised: 14 July 2017 / Accepted: 14 July 2017 / Published: 19 July 2017

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Abstract

Metabolic syndrome (MetS) is a group of related metabolic alterations that increase the risk of developing non-alcoholic fatty liver disease (NAFLD). Several lifestyle interventions based on dietary treatment with functional ingredients and physical activity are being studied as alternative or reinforcement treatments to

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Metabolic syndrome (MetS) is a group of related metabolic alterations that increase the risk of developing non-alcoholic fatty liver disease (NAFLD). Several lifestyle interventions based on dietary treatment with functional ingredients and physical activity are being studied as alternative or reinforcement treatments to the pharmacological ones actually in use. In the present experiment, the combined treatment with mung bean (Vigna radiata), a widely used legume with promising nutritional and health benefits that was included in the experimental diet as raw or 4 day-germinated seed flour, and aerobic interval training protocol (65–85% VO₂ max) has been tested in lean and obese Zucker rats following a 2 × 2 × 2 (2 phenotypes, 2 dietary interventions, 2 lifestyles) factorial ANOVA (Analysis of Variance) statistical analysis. Germination of V. radiata over a period of four days originated a significant protein hydrolysis leading to the appearance of low molecular weight peptides. The combination of 4 day-germinated V. radiata and aerobic interval training was more efficient compared to raw V. radiata at improving the aerobic capacity and physical performance, hepatic histology and functionality, and plasma lipid parameters as well as reverting the insulin resistance characteristic of the obese Zucker rat model. In conclusion, the joint intervention with legume sprouts and aerobic interval training protocol is an efficient treatment to improve the alterations of glucose and lipid metabolism as well as hepatic histology and functionality related to the development of NAFLD and the MetS. Full article

(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)

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Open AccessArticle Phyllanthus Niruri Standardized Extract Alleviates the Progression of Non-Alcoholic Fatty Liver Disease and Decreases Atherosclerotic Risk in Sprague–Dawley Rats

by Raghdaa Hamdan Al Zarzour, Mariam Ahmad, Mohd. Zaini Asmawi, Gurjeet Kaur, Mohammed Ali Ahmed Saeed, Majed Ahmed Al-Mansoub, Sultan Ayesh Mohammed Saghir, Nasiba Salisu Usman, Dhamraa W. Al-Dulaimi and Mun Fei Yam

Nutrients 2017, 9(7), 766; doi:10.3390/nu9070766

Received: 16 May 2017 / Revised: 19 June 2017 / Accepted: 12 July 2017 / Published: 18 July 2017

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the major global health issues, strongly correlated with insulin resistance, obesity and oxidative stress. The current study aimed to evaluate anti-NAFLD effects of three different extracts of Phyllanthus niruri (P. niruri). NAFLD

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Non-alcoholic fatty liver disease (NAFLD) is one of the major global health issues, strongly correlated with insulin resistance, obesity and oxidative stress. The current study aimed to evaluate anti-NAFLD effects of three different extracts of Phyllanthus niruri (P. niruri). NAFLD was induced in male Sprague–Dawley rats using a special high-fat diet (HFD). A 50% methanolic extract (50% ME) exhibited the highest inhibitory effect against NAFLD progression. It significantly reduced hepatomegaly (16%) and visceral fat weight (22%), decreased NAFLD score, prevented fibrosis, and reduced serum total cholesterol (TC) (48%), low-density lipoprotein (LDL) (65%), free fatty acids (FFAs) (25%), alanine aminotransferase (ALT) (45%), alkaline phosphatase (ALP) (38%), insulin concentration (67%), homeostatic model assessment of insulin resistance (HOMA-IR) (73%), serum atherogenic ratios TC/high-density lipoprotein (HDL) (29%), LDL/HDL (66%) and (TC–HDL)/HDL (64%), hepatic content of cholesterol (43%), triglyceride (29%) and malondialdehyde (MDA) (40%) compared to a non-treated HFD group. In vitro, 50% ME of P. niruri inhibited α-glucosidase, pancreatic lipase enzymes and cholesterol micellization. It also had higher total phenolic and total flavonoid contents compared to other extracts. Ellagic acid and phyllanthin were identified as major compounds. These results suggest that P. niruri could be further developed as a novel natural hepatoprotective agent against NAFLD and atherosclerosis. Full article

(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)

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Open AccessArticle Genetic Contribution to Alcohol Dependence: Investigation of a Heterogeneous German Sample of Individuals with Alcohol Dependence, Chronic Alcoholic Pancreatitis, and Alcohol-Related Cirrhosis

Genes 2017, 8(7), 183; doi:10.3390/genes8070183

Received: 27 June 2017 / Accepted: 11 July 2017 / Published: 17 July 2017

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Abstract

The present study investigated the genetic contribution to alcohol dependence (AD) using genome-wide association data from three German samples. These comprised patients with: (i) AD; (ii) chronic alcoholic pancreatitis (ACP); and (iii) alcohol-related liver cirrhosis (ALC). Single marker, gene-based, and pathway analyses were

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The present study investigated the genetic contribution to alcohol dependence (AD) using genome-wide association data from three German samples. These comprised patients with: (i) AD; (ii) chronic alcoholic pancreatitis (ACP); and (iii) alcohol-related liver cirrhosis (ALC). Single marker, gene-based, and pathway analyses were conducted. A significant association was detected for the ADH1B locus in a gene-based approach (p_uncorrected = 1.2 × 10⁻⁶; p_corrected = 0.020). This was driven by the AD subsample. No association with ADH1B was found in the combined ACP + ALC sample. On first inspection, this seems surprising, since ADH1B is a robustly replicated risk gene for AD and may therefore be expected to be associated also with subgroups of AD patients. The negative finding in the ACP + ALC sample, however, may reflect genetic stratification as well as random fluctuation of allele frequencies in the cases and controls, demonstrating the importance of large samples in which the phenotype is well assessed. Full article

(This article belongs to the Section Human Genetics and Genomics)

Open AccessReview The Association between Non-Alcoholic Fatty Liver Disease and Cardiovascular Risk in Children

by Anna Di Sessa, Giuseppina Rosaria Umano and Emanuele Miraglia del Giudice

Children 2017, 4(7), 57; doi:10.3390/children4070057

Received: 28 April 2017 / Revised: 28 June 2017 / Accepted: 3 July 2017 / Published: 7 July 2017

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Abstract

The rising prevalence of childhood obesity in the past decades has made Non-Alcoholic Fatty Liver Disease (NAFLD) the most common cause of pediatric chronic liver disease worldwide. Currently, a growing body of evidence links NAFLD with cardiovascular disease (CVD) even at an early

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The rising prevalence of childhood obesity in the past decades has made Non-Alcoholic Fatty Liver Disease (NAFLD) the most common cause of pediatric chronic liver disease worldwide. Currently, a growing body of evidence links NAFLD with cardiovascular disease (CVD) even at an early age. Data on the pediatric population have shown that NAFLD could represent an independent risk factor not only for cardiovascular events but also for early subclinical abnormalities in myocardial structure and function. Briefly, we review the current knowledge regarding the relationship between pediatric NAFLD and cardiovascular risk in an attempt to clarify our understanding of NAFLD as a possible cardiovascular risk factor in childhood. Full article

(This article belongs to the Special Issue Pediatric Nonalcoholic Fatty Liver Disease)

Open AccessArticle A Relative Deficiency of Lysosomal Acid Lypase Activity Characterizes Non-Alcoholic Fatty Liver Disease

by Francesco Tovoli, Lucia Napoli, Giulia Negrini, Sergio D’Addato, Giulia Tozzi, Jessica D’Amico, Fabio Piscaglia and Luigi Bolondi

Int. J. Mol. Sci. 2017, 18(6), 1134; doi:10.3390/ijms18061134

Received: 20 April 2017 / Revised: 15 May 2017 / Accepted: 22 May 2017 / Published: 25 May 2017

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Abstract

Lysosomal acid lipase (LAL) is a key enzyme in lipid metabolism. Initial reports have suggested a role for a relative acquired LAL deficiency in non-alcoholic fatty liver disease (NAFLD)—however, it is still unclear whether this mechanism is specific for NAFLD. We aimed to

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Lysosomal acid lipase (LAL) is a key enzyme in lipid metabolism. Initial reports have suggested a role for a relative acquired LAL deficiency in non-alcoholic fatty liver disease (NAFLD)—however, it is still unclear whether this mechanism is specific for NAFLD. We aimed to determine LAL activity in a cohort of NAFLD subjects and in a control group of hepatitis C virus (HCV)-infected patients, investigating the role of liver cirrhosis. A total of 81 patients with a diagnosis of NAFLD, and 78 matched controls with HCV-related liver disease were enrolled. For each patient, LAL activity was determined on peripheral dried blood spots (DBS) and correlated with clinical and laboratory data. A subgroup analysis among cirrhotic patients was also performed. LAL activity is significantly reduced in NAFLD, compared to that in HCV patients. This finding is particularly evident in the pre-cirrhotic stage of disease. LAL activity is also correlated with platelet and white blood cell count, suggesting an analytic interference of portal-hypertension-induced pancytopenia on DBS-determined LAL activity. NAFLD is characterized by a specific deficit in LAL activity, suggesting a pathogenetic role of LAL. We propose that future studies on this topic should rely on tissue specific analyses, as peripheral blood tests are also influenced by confounding factors. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Open AccessArticle Long Non-Coding RNA Profiling in a Non-Alcoholic Fatty Liver Disease Rodent Model: New Insight into Pathogenesis

by Yi Chen, Haixiu Huang, Chengfu Xu, Chaohui Yu and Youming Li

Int. J. Mol. Sci. 2017, 18(1), 21; doi:10.3390/ijms18010021

Received: 29 September 2016 / Revised: 9 December 2016 / Accepted: 9 December 2016 / Published: 16 January 2017

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases worldwide with an unclear mechanism. Long non-coding RNAs (lncRNAs) have recently emerged as important regulatory molecules. To better understand NAFLD pathogenesis, lncRNA and messenger RNA (mRNA) microarrays were conducted

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Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases worldwide with an unclear mechanism. Long non-coding RNAs (lncRNAs) have recently emerged as important regulatory molecules. To better understand NAFLD pathogenesis, lncRNA and messenger RNA (mRNA) microarrays were conducted in an NAFLD rodent model. Potential target genes of significantly changed lncRNA were predicted using cis/trans-regulatory algorithms. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed to explore their function. In the current analysis, 89 upregulated and 177 downregulated mRNAs were identified, together with 291 deregulated lncRNAs. Bioinformatic analysis of these RNAs has categorized these RNAs into pathways including arachidonic acid metabolism, circadian rhythm, linoleic acid metabolism, peroxisome proliferator-activated receptor (PPAR) signaling pathway, sphingolipid metabolism, steroid biosynthesis, tryptophan metabolism and tyrosine metabolism were compromised. Quantitative polymerase chain reaction (qPCR) of representative nine mRNAs and eight lncRNAs (named fatty liver-related lncRNA, FLRL) was conducted and this verified previous microarray results. Several lncRNAs, such as FLRL1, FLRL6 and FLRL2 demonstrated to be involved in circadian rhythm targeting period circadian clock 3 (Per3), Per2 and aryl hydrocarbon receptor nuclear translocator-like (Arntl), respectively. While FLRL8, FLRL3 and FLRL7 showed a potential role in PPAR signaling pathway through interaction with fatty acid binding protein 5 (Fabp5), lipoprotein lipase (Lpl) and fatty acid desaturase 2 (Fads2). Functional experiments showed that interfering of lncRNA FLRL2 expression affected the expression of predicted target, circadian rhythm gene Arntl. Moreover, both FLRL2 and Arntl were downregulated in the NAFLD cellular model. The current study identified lncRNA and corresponding mRNA in NAFLD, providing new insight into the pathogenesis of NAFLD. Moreover, we identified a new lncRNA FLRL2, that might participate NAFLD pathogenesis mediated by Arntl. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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Open AccessArticle Increased Expression Profile and Functionality of TLR6 in Peripheral Blood Mononuclear Cells and Hepatocytes of Morbidly Obese Patients with Non-Alcoholic Fatty Liver Disease

by María Teresa Arias-Loste, Paula Iruzubieta, Ángela Puente, David Ramos, Carolina Santa Cruz, Ángel Estébanez, Susana Llerena, Carmen Alonso-Martín, David San Segundo, Lorena Álvarez, Antonio López Useros, Emilio Fábrega, Marcos López-Hoyos and Javier Crespo

Int. J. Mol. Sci. 2016, 17(11), 1878; doi:10.3390/ijms17111878

Received: 14 September 2016 / Revised: 31 October 2016 / Accepted: 2 November 2016 / Published: 10 November 2016

Abstract

Current evidence suggests that gut dysbiosis drives obesity and non-alcoholic fatty liver disease (NAFLD) pathogenesis. Toll-like receptor 2 (TLR2) and TLR6 specifically recognize components of Gram-positive bacteria. Despite the potential implications of TLR2 in NAFLD pathogenesis, the role of TLR6 has not been

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Current evidence suggests that gut dysbiosis drives obesity and non-alcoholic fatty liver disease (NAFLD) pathogenesis. Toll-like receptor 2 (TLR2) and TLR6 specifically recognize components of Gram-positive bacteria. Despite the potential implications of TLR2 in NAFLD pathogenesis, the role of TLR6 has not been addressed. Our aim is to study a potential role of TLR6 in obesity-related NAFLD. Forty morbidly obese patients undergoing bariatric surgery were prospectively studied. Cell surface expression of TLR2 and TLR6 was assessed on peripheral blood mononuclear cells (PBMCs) by flow cytometry. Freshly isolated monocytes were cultured with specific TLR2/TLR6 agonists and intracellular production of cytokines was determined by flow-cytometry. In liver biopsies, the expression of TLR2 and TLR6 was analyzed by immunohistochemistry and cytokine gene expression using RT-qPCR. TLR6 expression in PBMCs from non-alcoholic steatohepatitis (NASH) patients was significantly higher when compared to those from simple steatosis. The production of pro-inflammatory cytokines in response to TLR2/TLR6 stimulation was also significantly higher in patients with lobular inflammation. Hepatocyte expression of TLR6 but not that of TLR2 was increased in NAFLD patients compared to normal liver histology. Deregulated expression and activity of peripheral TLR6 in morbidly obese patients can mirror the liver inflammatory events that are well known drivers of obesity-related NASH pathogenesis. Moreover, TLR6 is also significantly overexpressed in the hepatocytes of NAFLD patients compared to their normal counterparts. Thus, deregulated TLR6 expression may potentiate TLR2-mediated liver inflammation in NAFLD pathogenesis, and also serve as a potential peripheral biomarker of obesity-related NASH. Full article

(This article belongs to the collection Molecular Mechanisms of Human Liver Diseases)

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Open AccessReview The Potential of Non-Provitamin A Carotenoids for the Prevention and Treatment of Non-Alcoholic Fatty Liver Disease

by Ana Gabriela Murillo, Diana M. DiMarco and Maria Luz Fernandez

Biology 2016, 5(4), 42; doi:10.3390/biology5040042

Received: 23 September 2016 / Revised: 24 October 2016 / Accepted: 3 November 2016 / Published: 8 November 2016

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is an obesity-associated spectrum of comorbidities defined by the presence of metabolic dysfunction, oxidative stress, inflammation, and fibrosis in the liver. If left untreated, NAFLD can progress to cirrhosis, liver failure, or hepatocellular carcinoma. NAFLD is recognized as

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Non-alcoholic fatty liver disease (NAFLD) is an obesity-associated spectrum of comorbidities defined by the presence of metabolic dysfunction, oxidative stress, inflammation, and fibrosis in the liver. If left untreated, NAFLD can progress to cirrhosis, liver failure, or hepatocellular carcinoma. NAFLD is recognized as the most common liver disease in the United States, affecting around 30% of the population. Identification of dietary components capable of reducing or preventing NAFLD is therefore essential to battle this condition. Dietary carotenoids including astaxanthin, lycopene, lutein, and zeaxanthin have been demonstrated to be potent antioxidants as well as to exhibit anti-inflammatory effects. Many studies report the protective effect(s) of these carotenoids against different conditions such as atherosclerosis, diabetic complications, age-related macular degeneration, and liver diseases. In this review, we will focus on the effects of these carotenoids in the prevention or reduction of NAFLD as seen in epidemiological observations and clinical trials, as well as the suggested mechanism of action derived from animal and cell studies. Full article

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Open AccessArticle Composition and Nutrient Information of Non-Alcoholic Beverages in the Spanish Market: An Update

by María Serrano Iglesias, María de Lourdes Samaniego Vaesken and Gregorio Varela Moreiras

Nutrients 2016, 8(10), 618; doi:10.3390/nu8100618

Received: 5 July 2016 / Revised: 21 September 2016 / Accepted: 26 September 2016 / Published: 8 October 2016

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Abstract

The aim of this study was to draw an updated map of the nutrition facts in the different categories of non-alcoholic beverages in the Spanish market based on the information declared on the labels of these products; we expect this first step to

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The aim of this study was to draw an updated map of the nutrition facts in the different categories of non-alcoholic beverages in the Spanish market based on the information declared on the labels of these products; we expect this first step to justify the need for the coordination and harmonization of food composition tables in Spain so that there will be an updated database available to produce realistic scientific nutrient intake estimates in accordance with the actual market scenario. Materials and Methods: The nutrition facts declared on the labels of non-alcoholic beverages by manufacturers in Spain were compiled and studied. Results: The database included 211 beverages classified in 7 groups with energy/carbohydrate content per 100 mL ranging from 0–55 kcal/0–13 g for soft drinks; 2–60 kcal/0–14.5 g for energy drinks; 24–31 kcal/5.8–7.5 g for sports drinks; 1–32 kcal/0–7.3 g for drinks containing mineral salts in their composition; 14–69 kcal/2.6–17 g for fruit juice, nectar, and grape musts; 43–78 kcal/6.1–14.4 g for vegetable drinks; and 33–88 kcal/3.6–14 g for dairy drinks. Conclusion: The current non-alcoholic beverage market is a dynamic, growing, and highly innovative one, allowing consumers to choose according to their preferences, needs, or level of physical activity at any moment of the day. Full article

Open AccessArticle Relationship between Methyl Tertiary Butyl Ether Exposure and Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study among Petrol Station Attendants in Southern China

by Jianping Yang, Qinzhi Wei, Xiaochun Peng, Xiaowu Peng, Jianhui Yuan and Dalin Hu

Int. J. Environ. Res. Public Health 2016, 13(10), 946; doi:10.3390/ijerph13100946

Received: 24 July 2016 / Revised: 7 September 2016 / Accepted: 20 September 2016 / Published: 23 September 2016

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Abstract

Methyl tertiary butyl ether (MTBE)—A well known gasoline additive substituting for lead alkyls—causes lipid disorders and liver dysfunctions in animal models. However, whether MTBE exposure is a risk factor for non-alcoholic fatty liver disease (NAFLD) remains uncertain. We evaluate the possible relationship between

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Methyl tertiary butyl ether (MTBE)—A well known gasoline additive substituting for lead alkyls—causes lipid disorders and liver dysfunctions in animal models. However, whether MTBE exposure is a risk factor for non-alcoholic fatty liver disease (NAFLD) remains uncertain. We evaluate the possible relationship between MTBE exposure and the prevalence of NAFLD among 71 petrol station attendants in southern China. The personal exposure concentrations of MTBE were analyzed by Head Space Solid Phase Microextraction GC/MS. NAFLD was diagnosed by using abdominal ultrasonography according to the guidelines for the diagnosis and treatment of NAFLD suggested by the Chinese Hepatology Association. Demographic and clinical characteristics potentially associated with NAFLD were investigated. Mutivariate logistic regression analysis was applied to measure odds ratios and 95% confidence intervals (CI). The result showed that the total prevalence of NAFLD was 15.49% (11/71) among the study subjects. The average exposure concentrations of MTBE were 292.98 ± 154.90 μg/m³ and 286.64 ± 122.28 μg/m³ in NAFLD and non-NAFLD groups, respectively, and there was no statistically significant difference between them (p > 0.05). After adjusting for age, gender, physical exercise, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), alanine aminotransferase (ALT), white blood cell (WBC), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), the odds ratios were 1.31 (95% CI: 0.85–1.54; p > 0.05), 1.14 (95% CI: 0.81–1.32; p > 0.05), 1.52 (95% CI: 0.93–1.61; p > 0.05) in the groups (including men and women) with exposure concentrations of MTBE of 100–200 μg/m³, 200–300 μg/m³, and ≥300 μg/m³, respectively, as compared to the group (including men and women) ≤100 μg/m³. Our investigation indicates that exposure to MTBE does not seem to be a significant risk factor for the prevalence of NAFLD among petrol station attendants in southern China. Full article

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Open AccessReview Effects of Probiotics and Synbiotics on Obesity, Insulin Resistance Syndrome, Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease: A Review of Human Clinical Trials

by Maria Jose Sáez-Lara, Candido Robles-Sanchez, Francisco Javier Ruiz-Ojeda, Julio Plaza-Diaz and Angel Gil

Int. J. Mol. Sci. 2016, 17(6), 928; doi:10.3390/ijms17060928

Received: 16 April 2016 / Revised: 24 May 2016 / Accepted: 2 June 2016 / Published: 13 June 2016

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Abstract

The use of probiotics and synbiotics in the prevention and treatment of different disorders has dramatically increased over the last decade. Both probiotics and synbiotics are well known ingredients of functional foods and nutraceuticals and may provide beneficial health effects because they can

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The use of probiotics and synbiotics in the prevention and treatment of different disorders has dramatically increased over the last decade. Both probiotics and synbiotics are well known ingredients of functional foods and nutraceuticals and may provide beneficial health effects because they can influence the intestinal microbial ecology and immunity. The present study reviews the effects of probiotics and synbiotics on obesity, insulin resistance syndrome (IRS), type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) in human randomized clinical trials. Select probiotics and synbiotics provided beneficial effects in patients with obesity, mainly affecting the body mass index and fat mass. Some probiotics had beneficial effects on IRS, decreasing the cell adhesion molecule-1 levels, and the synbiotics decreased the insulin resistance and plasma lipid levels. Moreover, select probiotics improved the carbohydrate metabolism, fasting blood glucose, insulin sensitivity and antioxidant status and also reduced metabolic stress in subjects with T2D. Some probiotics and synbiotics improved the liver and metabolic parameters in patients with NAFLD. The oral intake of probiotics and synbiotics as co-adjuvants for the prevention and treatment of obesity, IRS, T2D and NAFLD is partially supported by the data shown in the present review. However, further studies are required to understand the precise mechanism of how probiotics and synbiotics affect these metabolic disorders. Full article

(This article belongs to the Special Issue Advances in Molecular Research of Functional and Nutraceutical Food)

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Open AccessReview Alcoholic Beverage Consumption and Chronic Diseases

by Yue Zhou, Jie Zheng, Sha Li, Tong Zhou, Pei Zhang and Hua-Bin Li

Int. J. Environ. Res. Public Health 2016, 13(6), 522; doi:10.3390/ijerph13060522

Received: 13 January 2016 / Revised: 12 May 2016 / Accepted: 16 May 2016 / Published: 24 May 2016

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Abstract

Epidemiological and experimental studies have consistently linked alcoholic beverage consumption with the development of several chronic disorders, such as cancer, cardiovascular diseases, diabetes mellitus and obesity. The impact of drinking is usually dose-dependent, and light to moderate drinking tends to lower risks of

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Epidemiological and experimental studies have consistently linked alcoholic beverage consumption with the development of several chronic disorders, such as cancer, cardiovascular diseases, diabetes mellitus and obesity. The impact of drinking is usually dose-dependent, and light to moderate drinking tends to lower risks of certain diseases, while heavy drinking tends to increase the risks. Besides, other factors such as drinking frequency, genetic susceptibility, smoking, diet, and hormone status can modify the association. The amount of ethanol in alcoholic beverages is the determining factor in most cases, and beverage types could also make an influence. This review summarizes recent studies on alcoholic beverage consumption and several chronic diseases, trying to assess the effects of different drinking patterns, beverage types, interaction with other risk factors, and provide mechanistic explanations. Full article

(This article belongs to the Special Issue Advances in Substance and Drug Abuse Prevention)

Open AccessReview The Natural Course of Non-Alcoholic Fatty Liver Disease

by Luis Calzadilla Bertot and Leon Anton Adams

Int. J. Mol. Sci. 2016, 17(5), 774; doi:10.3390/ijms17050774

Received: 29 April 2016 / Revised: 12 May 2016 / Accepted: 12 May 2016 / Published: 20 May 2016

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, paralleling the epidemic of obesity and Type 2 diabetes mellitus (T2DM). NAFLD exhibits a histological spectrum, ranging from “bland steatosis” to the more aggressive necro-inflammatory form,

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Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, paralleling the epidemic of obesity and Type 2 diabetes mellitus (T2DM). NAFLD exhibits a histological spectrum, ranging from “bland steatosis” to the more aggressive necro-inflammatory form, non-alcoholic steatohepatitis (NASH) which may accumulate fibrosis to result in cirrhosis. Emerging data suggests fibrosis, rather than NASH per se, to be the most important histological predictor of liver and non-liver related death. Nevertheless, only a small proportion of individuals develop cirrhosis, however the large proportion of the population affected by NAFLD has led to predictions that NAFLD will become a leading cause of end stage liver disease, hepatocellular carcinoma (HCC), and indication for liver transplantation. HCC may arise in non-cirrhotic liver in the setting of NAFLD and is associated with the presence of the metabolic syndrome (MetS) and male gender. The MetS and its components also play a key role in the histological progression of NAFLD, however other genetic and environmental factors may also influence the natural history. The importance of NAFLD in terms of overall survival extends beyond the liver where cardiovascular disease and malignancy represents additional important causes of death. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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Open AccessArticle PNPLA3 Expression Is Related to Liver Steatosis in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease

by Gemma Aragonès, Teresa Auguet, Sandra Armengol, Alba Berlanga, Esther Guiu-Jurado, Carmen Aguilar, Salomé Martínez, Fátima Sabench, José Antonio Porras, Maikel Daniel Ruiz, Mercé Hernández, Joan Josep Sirvent, Daniel Del Castillo and Cristóbal Richart

Int. J. Mol. Sci. 2016, 17(5), 630; doi:10.3390/ijms17050630

Received: 24 February 2016 / Revised: 19 April 2016 / Accepted: 22 April 2016 / Published: 27 April 2016

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Abstract

Recent reports suggest a role for the Patatin-like phospholipase domain-containing protein 3 (PNPLA3) in the pathology of non-alcoholic fatty liver disease (NAFLD). Lipid deposition in the liver seems to be a critical process in the pathogenesis of NAFLD. The aim of the present

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Recent reports suggest a role for the Patatin-like phospholipase domain-containing protein 3 (PNPLA3) in the pathology of non-alcoholic fatty liver disease (NAFLD). Lipid deposition in the liver seems to be a critical process in the pathogenesis of NAFLD. The aim of the present work was to evaluate the association between the liver PNPLA3 expression, key genes of lipid metabolism, and the presence of NAFLD in morbidly obese women. We used real-time polymerase chain reaction (PCR) analysis to analyze the hepatic expression of PNPLA3 and lipid metabolism-related genes in 55 morbidly obese subjects with normal liver histology (NL, n = 18), simple steatosis (SS, n = 20), and non-alcoholic steatohepatitis (NASH, n = 17). Liver biopsies were collected during bariatric surgery. We observed that liver PNPLA3 expression was increased in NAFLD than in NL. It was also upregulated in SS than in NL. Interestingly, we found that the expression of PNPLA3 was significantly higher in severe than mild SS group. In addition, the expression of the transcription factors LXRα, PPARα, and SREBP2 was positively correlated with PNPLA3 liver expression. Regarding rs738409 polymorphism, GG genotype was positive correlated with the presence of NASH. In conclusion, our results show that PNPLA3 could be related to lipid accumulation in liver, mainly in the development and progression of simple steatosis. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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Open AccessReview Non-Alcoholic Fatty Liver Disease and Metabolic Syndrome after Liver Transplant

by Stefano Gitto and Erica Villa

Int. J. Mol. Sci. 2016, 17(4), 490; doi:10.3390/ijms17040490

Received: 16 March 2016 / Revised: 25 March 2016 / Accepted: 28 March 2016 / Published: 2 April 2016

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Abstract

Liver transplant is the unique curative therapy for patients with acute liver failure or end-stage liver disease, with or without hepatocellular carcinoma. Increase of body weight, onset of insulin resistance and drug-induced alterations of metabolism are reported in liver transplant recipients. In this

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Liver transplant is the unique curative therapy for patients with acute liver failure or end-stage liver disease, with or without hepatocellular carcinoma. Increase of body weight, onset of insulin resistance and drug-induced alterations of metabolism are reported in liver transplant recipients. In this context, post-transplant diabetes mellitus, hyperlipidemia, and arterial hypertension can be often diagnosed. Multifactorial illnesses occurring in the post-transplant period represent significant causes of morbidity and mortality. This is especially true for metabolic syndrome. Non-alcoholic steatosis and steatohepatitis are hepatic manifestations of metabolic syndrome and after liver transplant both recurrent and de novo steatosis can be found. Usually, post-transplant steatosis shows an indolent outcome with few cases of fibrosis progression. However, in the post-transplant setting, both metabolic syndrome and steatosis might play a key role in the stratification of morbidity and mortality risk, being commonly associated with cardiovascular disease. The single components of metabolic syndrome can be treated with targeted drugs while lifestyle intervention is the only reasonable therapeutic approach for transplant patients with non-alcoholic steatosis or steatohepatitis. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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Open AccessArticle Additive Effect of Non-Alcoholic Fatty Liver Disease on Metabolic Syndrome-Related Endothelial Dysfunction in Hypertensive Patients

by Maria Perticone, Antonio Cimellaro, Raffaele Maio, Benedetto Caroleo, Angela Sciacqua, Giorgio Sesti and Francesco Perticone

Int. J. Mol. Sci. 2016, 17(4), 456; doi:10.3390/ijms17040456

Received: 28 February 2016 / Revised: 16 March 2016 / Accepted: 22 March 2016 / Published: 26 March 2016

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Abstract

Metabolic syndrome (MS) is characterized by an increased risk of incident diabetes and cardiovascular (CV) events, identifying insulin resistance (IR) and endothelial dysfunction as key elements. Moreover, non-alcoholic fatty liver disease (NAFLD) is bidirectionally linked with MS as a consequence of metabolic and

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Metabolic syndrome (MS) is characterized by an increased risk of incident diabetes and cardiovascular (CV) events, identifying insulin resistance (IR) and endothelial dysfunction as key elements. Moreover, non-alcoholic fatty liver disease (NAFLD) is bidirectionally linked with MS as a consequence of metabolic and inflammatory abnormalities. We addressed the question if the evolution in NAFLD might worsen endothelium-dependent vasodilating response in MS hypertensives. We recruited 272 Caucasian newly-diagnosed never-treated hypertensive outpatients divided into three groups according to the presence/absence of MS alone or in combination with NAFLD. MS and NAFLD were defined according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) and non-invasive fatty liver index, respectively. We determined IR by using the homeostasis model assessment (HOMA) index. Vascular function, as forearm blood flow (FBF), was determined through strain-gauge plethysmography after intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside. MS+NAFLD+ group showed worse metabolic, inflammatory and vascular profiles compared with MS−NAFLD− and MS+NAFLD−. HOMA resulted in being the strongest predictor of FBF both in the MS+NAFLD− and in the MS+NAFLD+ groups, accounting for 20.5% and 33.2% of its variation, respectively. In conclusion, we demonstrated that MS+NAFLD+ hypertensives show a worse endothelium-dependent vasodilation compared with MS+NAFLD−, allowing for consideration of NAFLD as an early marker of endothelial dysfunction in hypertensives. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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Open AccessReview Extracellular Vesicles: A New Frontier in Biomarker Discovery for Non-Alcoholic Fatty Liver Disease

by Linda A. Ban, Nicholas A. Shackel and Susan V. McLennan

Int. J. Mol. Sci. 2016, 17(3), 376; doi:10.3390/ijms17030376

Received: 24 February 2016 / Revised: 1 March 2016 / Accepted: 2 March 2016 / Published: 14 March 2016

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Abstract

In recent years, the global burden of obesity and diabetes has seen a parallel rise in other metabolic complications, such as non-alcoholic fatty liver disease (NAFLD). This condition, once thought to be a benign accumulation of hepatic fat, is now recognized as a

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In recent years, the global burden of obesity and diabetes has seen a parallel rise in other metabolic complications, such as non-alcoholic fatty liver disease (NAFLD). This condition, once thought to be a benign accumulation of hepatic fat, is now recognized as a serious and prevalent disorder that is conducive to inflammation and fibrosis. Despite the rising incidence of NAFLD, there is currently no reliable method for its diagnosis or staging besides the highly invasive tissue biopsy. This limitation has resulted in the study of novel circulating markers as potential candidates, one of the most popular being extracellular vesicles (EVs). These submicron membrane-bound structures are secreted from stressed and activated cells, or are formed during apoptosis, and are known to be involved in intercellular communication. The cargo of EVs depends upon the parent cell and has been shown to be changed in disease, as is their abundance in the circulation. The role of EVs in immunity and epigenetic regulation is widely attested, and studies showing a correlation with disease severity have made these structures a favorable target for diagnostic as well as therapeutic purposes. This review will highlight the research that is available on EVs in the context of NAFLD, the current limitations, and projections for their future utility in a clinical setting. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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Open AccessReview Alcoholic Liver Disease: Update on the Role of Dietary Fat

by Irina A. Kirpich, Matthew E. Miller, Matthew C. Cave, Swati Joshi-Barve and Craig J. McClain

Biomolecules 2016, 6(1), 1; doi:10.3390/biom6010001

Received: 31 August 2015 / Revised: 23 November 2015 / Accepted: 7 December 2015 / Published: 6 January 2016

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Abstract

Alcoholic liver disease (ALD) spans a spectrum of liver pathology, including fatty liver, alcoholic steatohepatitis, and cirrhosis. Accumulating evidence suggests that dietary factors, including dietary fat, as well as alcohol, play critical roles in the pathogenesis of ALD. The protective effects of dietary

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Alcoholic liver disease (ALD) spans a spectrum of liver pathology, including fatty liver, alcoholic steatohepatitis, and cirrhosis. Accumulating evidence suggests that dietary factors, including dietary fat, as well as alcohol, play critical roles in the pathogenesis of ALD. The protective effects of dietary saturated fat (SF) and deleterious effects of dietary unsaturated fat (USF) on alcohol-induced liver pathology are well recognized and documented in experimental animal models of ALD. Moreover, it has been demonstrated in an epidemiological study of alcoholic cirrhosis that dietary intake of SF was associated with a lower mortality rates, whereas dietary intake of USF was associated with a higher mortality. In addition, oxidized lipids (dietary and in vivo generated) may play a role in liver pathology. The understanding of how dietary fat contributes to the ALD pathogenesis will enhance our knowledge regarding the molecular mechanisms of ALD development and progression, and may result in the development of novel diet-based therapeutic strategies for ALD management. This review explores the relevant scientific literature and provides a current understanding of recent advances regarding the role of dietary lipids in ALD pathogenesis. Full article

(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)

Open AccessArticle The Dipeptidyl Peptidase-4 Inhibitor Teneligliptin Attenuates Hepatic Lipogenesis via AMPK Activation in Non-Alcoholic Fatty Liver Disease Model Mice

by Takayasu Ideta, Yohei Shirakami, Tsuneyuki Miyazaki, Takahiro Kochi, Hiroyasu Sakai, Hisataka Moriwaki and Masahito Shimizu

Int. J. Mol. Sci. 2015, 16(12), 29207-29218; doi:10.3390/ijms161226156

Received: 19 October 2015 / Revised: 24 November 2015 / Accepted: 30 November 2015 / Published: 8 December 2015

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Abstract

Non-alcoholic fatty liver disease (NAFLD), which is strongly associated with metabolic syndrome, is increasingly a major cause of hepatic disorder. Dipeptidyl peptidase (DPP)-4 inhibitors, anti-diabetic agents, are expected to be effective for the treatment of NAFLD. In the present study, we established a

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Non-alcoholic fatty liver disease (NAFLD), which is strongly associated with metabolic syndrome, is increasingly a major cause of hepatic disorder. Dipeptidyl peptidase (DPP)-4 inhibitors, anti-diabetic agents, are expected to be effective for the treatment of NAFLD. In the present study, we established a novel NAFLD model mouse using monosodium glutamate (MSG) and a high-fat diet (HFD) and investigated the effects of a DPP-4 inhibitor, teneligliptin, on the progression of NAFLD. Male MSG/HFD-treated mice were divided into two groups, one of which received teneligliptin in drinking water. Administration of MSG and HFD caused mice to develop severe fatty changes in the liver, but teneligliptin treatment improved hepatic steatosis and inflammation, as evaluated by the NAFLD activity score. Serum alanine aminotransferase and intrahepatic triglyceride levels were significantly decreased in teneligliptin-treated mice (p < 0.05). Hepatic mRNA levels of the genes involved in de novo lipogenesis were significantly downregulated by teneligliptin (p < 0.05). Moreover, teneligliptin increased hepatic expression levels of phosphorylated AMP-activated protein kinase (AMPK) protein. These findings suggest that teneligliptin attenuates lipogenesis in the liver by activating AMPK and downregulating the expression of genes involved in lipogenesis. DPP-4 inhibitors may be effective for the treatment of NAFLD and may be able to prevent its progression to non-alcoholic steatohepatitis. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

Open AccessArticle Assessment of Diet and Physical Activity in Paediatric Non-Alcoholic Fatty Liver Disease Patients: A United Kingdom Case Control Study

by Philippa S. Gibson, Sarah Lang, Marianne Gilbert, Deepa Kamat, Sanjay Bansal, Martha E. Ford-Adams, Ashish P. Desai, Anil Dhawan, Emer Fitzpatrick, J. Bernadette Moore and Kathryn H. Hart

Nutrients 2015, 7(12), 9721-9733; doi:10.3390/nu7125494

Received: 14 August 2015 / Revised: 9 October 2015 / Accepted: 11 November 2015 / Published: 26 November 2015

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children, with prevalence rising alongside childhood obesity rates. This study aimed to characterise the habitual diet and activity behaviours of children with NAFLD compared to obese children without

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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children, with prevalence rising alongside childhood obesity rates. This study aimed to characterise the habitual diet and activity behaviours of children with NAFLD compared to obese children without liver disease in the United Kingdom (UK). Twenty-four biopsy-proven paediatric NAFLD cases and eight obese controls without biochemical or radiological evidence of NAFLD completed a 24-h dietary recall, a Physical Activity Questionnaire (PAQ), a Dutch Eating Behavior Questionnaire (DEBQ) and a 7-day food and activity diary (FAD), in conjunction with wearing a pedometer. Groups were well matched for age and gender. Obese children had higher BMI z-scores (p = 0.006) and BMI centiles (p = 0.002) than participants with NAFLD. After adjusting for multiple hypotheses testing and controlling for differences in BMI, no differences in macro- or micronutrient intake were observed as assessed using either 24-h recall or 7-day FAD (p > 0.001). Under-reporting was prevalent (NAFLD 75%, Obese Control 87%: p = 0.15). Restrained eating behaviours were significantly higher in the NAFLD group (p = 0.005), who also recorded more steps per day than the obese controls (p = 0.01). In conclusion, this is the first study to assess dietary and activity patterns in a UK paediatric NAFLD population. Only a minority of cases and controls were meeting current dietary and physical activity recommendations. Our findings do not support development of specific dietary/ physical activity guidelines for children with NAFLD; promoting adherence with current general paediatric recommendations for health should remain the focus of clinical management. Full article

(This article belongs to the Special Issue Nutritional Approaches to the Prevention and Management of Childhood Obesity)

Open AccessReview Does Lysosomial Acid Lipase Reduction Play a Role in Adult Non-Alcoholic Fatty Liver Disease?

by Francesco Baratta, Daniele Pastori, Licia Polimeni, Giulia Tozzi, Francesco Violi, Francesco Angelico and Maria Del Ben

Int. J. Mol. Sci. 2015, 16(12), 28014-28021; doi:10.3390/ijms161226085

Received: 13 October 2015 / Revised: 6 November 2015 / Accepted: 17 November 2015 / Published: 25 November 2015

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Abstract

Lysosomal Acid Lipase (LAL) is a key enzyme involved in lipid metabolism, responsible for hydrolysing the cholesteryl esters and triglycerides. Wolman Disease represents the early onset phenotype of LAL deficiency rapidly leading to death. Cholesterol Ester Storage Disease is a late onset phenotype

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Lysosomal Acid Lipase (LAL) is a key enzyme involved in lipid metabolism, responsible for hydrolysing the cholesteryl esters and triglycerides. Wolman Disease represents the early onset phenotype of LAL deficiency rapidly leading to death. Cholesterol Ester Storage Disease is a late onset phenotype that occurs with fatty liver, elevated aminotransferase levels, hepatomegaly and dyslipidaemia, the latter characterized by elevated LDL-C and low HDL-C. The natural history and the clinical manifestations of the LAL deficiency in adults are not well defined, and the diagnosis is often incidental. LAL deficiency has been suggested as an under-recognized cause of dyslipidaemia and fatty liver. Therefore, LAL activity may be reduced also in non-obese patients presenting non-alcoholic fatty liver disease (NAFLD), unexplained persistently elevated liver transaminases or with elevation in LDL cholesterol. In these patients, it could be indicated to test LAL activity. So far, very few studies have been performed to assess LAL activity in representative samples of normal subjects or patients with NAFLD. Moreover, no large study has been carried out in adult subjects with NAFLD or cryptogenic cirrhosis. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

Open AccessReview Update on Alcoholic Hepatitis

by Natalie J. Torok

Biomolecules 2015, 5(4), 2978-2986; doi:10.3390/biom5042978

Received: 6 September 2015 / Revised: 26 October 2015 / Accepted: 29 October 2015 / Published: 2 November 2015

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Abstract

Alcoholic liver disease is one of the most prevalent liver diseases worldwide, and a major cause of morbidity and mortality. Alcoholic hepatitis is a severe form of liver injury in patients with alcohol abuse, can present as an acute on chronic liver failure

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Alcoholic liver disease is one of the most prevalent liver diseases worldwide, and a major cause of morbidity and mortality. Alcoholic hepatitis is a severe form of liver injury in patients with alcohol abuse, can present as an acute on chronic liver failure associated with a rapid decline in liver synthetic function, and consequent increase in mortality. Despite therapy, about 30%–50% of patients with severe alcoholic hepatitis eventually die. The pathogenic pathways that lead to the development of alcoholic hepatitis are complex and involve oxidative stress, gut dysbiosis, and dysregulation of the innate and adaptive immune system with injury to the parenchymal cells and activation of hepatic stellate cells. As accepted treatment approaches are currently limited, a better understanding of the pathophysiology would be required to generate new approaches that improve outcomes. This review focuses on recent advances in the diagnosis, pathogenesis of alcoholic hepatitis and novel treatment strategies. Full article

(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)

Open AccessReview Alcoholic Liver Disease: Role of Cytokines

by Manuela G. Neuman, Yaakov Maor, Radu M. Nanau, Ehud Melzer, Haim Mell, Mihai Opris, Lawrence Cohen and Stephen Malnick

Biomolecules 2015, 5(3), 2023-2034; doi:10.3390/biom5032023

Received: 3 July 2015 / Revised: 21 August 2015 / Accepted: 24 August 2015 / Published: 28 August 2015

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Abstract

The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical and translational research. It focuses on the role of the immune system and the signaling pathways of cytokines in the pathogenesis of ALD. An additional factor

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The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical and translational research. It focuses on the role of the immune system and the signaling pathways of cytokines in the pathogenesis of ALD. An additional factor that contributes to the pathogenesis of ALD is lipopolysaccharide (LPS), which plays a central role in the induction of steatosis, inflammation, and fibrosis in the liver. LPS derived from the intestinal microbiota enters the portal circulation, and is recognized by macrophages (Kupffer cells) and hepatocytes. In individuals with ALD, excessive levels of LPS in the liver affect immune, parenchymal, and non-immune cells, which in turn release various inflammatory cytokines and recruit neutrophils and other inflammatory cells. In this review, we elucidate the mechanisms by which alcohol contributes to the activation of Kupffer cells and the inflammatory cascade. The role of the stellate cells in fibrogenesis is also discussed. Full article

(This article belongs to the collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)

Open AccessReview Beverage Consumption: Are Alcoholic and Sugary Drinks Tipping the Balance towards Overweight and Obesity?

by Sally D. Poppitt

Nutrients 2015, 7(8), 6700-6718; doi:10.3390/nu7085304

Received: 5 March 2015 / Revised: 21 July 2015 / Accepted: 21 July 2015 / Published: 11 August 2015

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Abstract

The role that energy-containing beverages may play in the development of overweight and obesity remains highly controversial, in particular the alcoholic and sugar-sweetened beverages (SSB). Both of these beverage formats have been increasing as a percentage of the westernized diet over the past

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The role that energy-containing beverages may play in the development of overweight and obesity remains highly controversial, in particular the alcoholic and sugar-sweetened beverages (SSB). Both of these beverage formats have been increasing as a percentage of the westernized diet over the past 20 years, and both have contributed significantly to an increase in energy consumed in liquid form. Data from epidemiology and intervention studies however have long been contradictory, despite mechanistic evidence pointing towards poor compensation for addition of “liquid” energy from these two sources into the diet providing a strong rational for the balance to be tipped towards weight gain. Regulatory and government intervention has been increasing globally, particularly with respect to intake of SSBs in children. This narrative review presents evidence which both supports and refutes the link between alcohol and carbohydrate-containing liquids and the regulation of body weight, and investigates mechanisms which may underpin any relationship between increased beverage consumption and increased energy intake, body weight and adiposity. Full article

Open AccessArticle Dietary Patterns Modulate the Risk of Non-Alcoholic Fatty Liver Disease in Chinese Adults

by Chao-Qun Yang, Long Shu, Shuai Wang, Jia-Jia Wang, Yu Zhou, Yu-Jie Xuan and Su-Fang Wang

Nutrients 2015, 7(6), 4778-4791; doi:10.3390/nu7064778

Received: 13 March 2015 / Revised: 1 May 2015 / Accepted: 5 May 2015 / Published: 15 June 2015

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Abstract

Although previous studies reported the associations between the intakes of individual foods or nutrients and the risk of non-alcoholic fatty liver disease (NAFLD), the relationship between dietary patterns and NAFLD in the Chinese population has been rarely studied to date. This study aimed

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Although previous studies reported the associations between the intakes of individual foods or nutrients and the risk of non-alcoholic fatty liver disease (NAFLD), the relationship between dietary patterns and NAFLD in the Chinese population has been rarely studied to date. This study aimed to investigate the associations between dietary patterns and the risk of NAFLD in a middle-aged Chinese population. The Study subjects were 999 Chinese adults aged 45–60 years in the Anhui province who participated in the Hefei Nutrition and Health Study. Dietary intake was collected by a semi-quantitative food frequency questionnaire. NAFLD was defined as the presence of moderate-severe hepatic steatosis (by B-ultrasonic examination); the absence of excessive alcohol use (>20 g day⁻¹ in men and 10 g day⁻¹ in women); no use of steatogenic medications within the past six months; no exposure to hepatotoxins; and no history of bariatric surgery. Log-binomial regression analysis was used to examine the association between dietary patterns and NAFLD with adjustment of potential confounding variables. Out of 999 participants, 345 (34.5%) were classified as having NAFLD. Four major dietary patterns were identified: “Traditional Chinese”, “Animal food”, “Grains-vegetables” and “High-salt” dietary patterns. After adjusting for potential confounders, subjects in the highest quartile of the “Animal food” pattern scores had greater prevalence ratio for NAFLD (prevalence ratio (PR) = 1.354; 95% confidence interval (CI): 1.063–1.724; p < 0.05) than did those in the lowest quartile. After adjustment for body mass index (BMI), compared with the lowest quartile of the “Grains-vegetables” pattern, the highest quartile had a lower prevalence ratio for NAFLD (PR = 0.777; 95% CI: 0.618–0.977, p < 0.05). However, the “traditional Chinese” and “high-salt” dietary patterns showed no association with the risk of NAFLD. Our findings indicated that the “Animal food” dietary pattern was associated with an increased risk of NAFLD. Full article

(This article belongs to the Special Issue Dietary Pattern and Health)

Open AccessReview Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) Is a Novel Nutritional Therapeutic Target for Hyperlipidemia, Non-Alcoholic Fatty Liver Disease, and Atherosclerosis

by Gwang-woong Go

Nutrients 2015, 7(6), 4453-4464; doi:10.3390/nu7064453

Received: 5 March 2015 / Revised: 13 May 2015 / Accepted: 27 May 2015 / Published: 3 June 2015

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Abstract

Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of the low-density lipoprotein receptor family and has a unique structure, which facilitates its multiple functions as a co-receptor for Wnt/β-catenin signaling and as a ligand receptor for endocytosis. The role LRP6 plays in

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Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of the low-density lipoprotein receptor family and has a unique structure, which facilitates its multiple functions as a co-receptor for Wnt/β-catenin signaling and as a ligand receptor for endocytosis. The role LRP6 plays in metabolic regulation, specifically in the nutrient-sensing pathway, has recently garnered considerable interest. Patients carrying an LRP6 mutation exhibit elevated levels of LDL cholesterol, triglycerides, and fasting glucose, which cooperatively constitute the risk factors of metabolic syndrome and atherosclerosis. Since the discovery of this mutation, the general role of LRP6 in lipid homeostasis, glucose metabolism, and atherosclerosis has been thoroughly researched. These studies have demonstrated that LRP6 plays a role in LDL receptor-mediated LDL uptake. In addition, when the LRP6 mutant impaired Wnt-LRP6 signaling, hyperlipidemia, non-alcoholic fatty liver disease, and atherosclerosis developed. LRP6 regulates lipid homeostasis and body fat mass via the nutrient-sensing mechanistic target of the rapamycin (mTOR) pathway. Furthermore, the mutant LRP6 triggers atherosclerosis by activating platelet-derived growth factor (PDGF)-dependent vascular smooth muscle cell differentiation. This review highlights the exceptional opportunities to study the pathophysiologic contributions of LRP6 to metabolic syndrome and cardiovascular diseases, which implicate LRP6 as a latent regulator of lipid metabolism and a novel therapeutic target for nutritional intervention. Full article

(This article belongs to the Special Issue Lipoprotein Metabolism and Atherosclerosis)

Open AccessReview Potential Epigenetic Mechanism in Non-Alcoholic Fatty Liver Disease

by Chao Sun, Jian-Gao Fan and Liang Qiao

Int. J. Mol. Sci. 2015, 16(3), 5161-5179; doi:10.3390/ijms16035161

Received: 28 December 2014 / Revised: 14 February 2015 / Accepted: 25 February 2015 / Published: 5 March 2015

Cited by 16 | Viewed by 2365 | PDF Full-text (728 KB) | HTML Full-text | XML Full-text

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the liver. It ranges from simple steatosis to its more aggressive form, non-alcoholic steatohepatitis (NASH), which may develop into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC) if it persists for a

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Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the liver. It ranges from simple steatosis to its more aggressive form, non-alcoholic steatohepatitis (NASH), which may develop into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC) if it persists for a long time. However, the exact pathogenesis of NAFLD and the related metabolic disorders remain unclear. Epigenetic changes are stable alterations that take place at the transcriptional level without altering the underlying DNA sequence. DNA methylation, histone modifications and microRNA are among the most common forms of epigenetic modification. Epigenetic alterations are involved in the regulation of hepatic lipid metabolism, insulin resistance, mitochondrial damage, oxidative stress response, and the release of inflammatory cytokines, all of which have been implicated in the development and progression of NAFLD. This review summarizes the current advances in the potential epigenetic mechanism of NAFLD. Elucidation of epigenetic factors may facilitate the identification of early diagnositic biomarkers and development of therapeutic strategies for NAFLD. Full article

(This article belongs to the collection Molecular Mechanisms of Human Liver Diseases)

Open AccessReview The Role of Dietary Sugars and De novo Lipogenesis in Non-Alcoholic Fatty Liver Disease

by J. Bernadette Moore, Pippa J. Gunn and Barbara A. Fielding

Nutrients 2014, 6(12), 5679-5703; doi:10.3390/nu6125679

Received: 21 October 2014 / Revised: 28 November 2014 / Accepted: 1 December 2014 / Published: 10 December 2014

Cited by 37 | Viewed by 2658 | PDF Full-text (600 KB) | HTML Full-text | XML Full-text

Abstract

Dietary sugar consumption, in particular sugar-sweetened beverages and the monosaccharide fructose, has been linked to the incidence and severity of non-alcoholic fatty liver disease (NAFLD). Intervention studies in both animals and humans have shown large doses of fructose to be particularly lipogenic. While

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Dietary sugar consumption, in particular sugar-sweetened beverages and the monosaccharide fructose, has been linked to the incidence and severity of non-alcoholic fatty liver disease (NAFLD). Intervention studies in both animals and humans have shown large doses of fructose to be particularly lipogenic. While fructose does stimulate de novo lipogenesis (DNL), stable isotope tracer studies in humans demonstrate quantitatively that the lipogenic effect of fructose is not mediated exclusively by its provision of excess substrates for DNL. The deleterious metabolic effects of high fructose loads appear to be a consequence of altered transcriptional regulatory networks impacting intracellular macronutrient metabolism and altering signaling and inflammatory processes. Uric acid generated by fructose metabolism may also contribute to or exacerbate these effects. Here we review data from human and animal intervention and stable isotope tracer studies relevant to the role of dietary sugars on NAFLD development and progression, in the context of typical sugar consumption patterns and dietary recommendations worldwide. We conclude that the use of hypercaloric, supra-physiological doses in intervention trials has been a major confounding factor and whether or not dietary sugars, including fructose, at typically consumed population levels, effect hepatic lipogenesis and NAFLD pathogenesis in humans independently of excess energy remains unresolved. Full article

(This article belongs to the Special Issue Nutrition and Liver Disease)

Open AccessArticle Altered Fatty Acid Metabolism-Related Gene Expression in Liver from Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease

by Teresa Auguet, Alba Berlanga, Esther Guiu-Jurado, Salomé Martinez, José Antonio Porras, Gemma Aragonès, Fátima Sabench, Mercé Hernandez, Carmen Aguilar, Joan Josep Sirvent, Daniel Del Castillo and Cristóbal Richart

Int. J. Mol. Sci. 2014, 15(12), 22173-22187; doi:10.3390/ijms151222173

Received: 2 October 2014 / Revised: 25 November 2014 / Accepted: 25 November 2014 / Published: 2 December 2014

Cited by 17 | Viewed by 1888 | PDF Full-text (973 KB) | HTML Full-text | XML Full-text

Abstract

Lipid accumulation in the human liver seems to be a crucial mechanism in the pathogenesis and the progression of non-alcoholic fatty liver disease (NAFLD). We aimed to evaluate gene expression of different fatty acid (FA) metabolism-related genes in morbidly obese (MO) women with

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Lipid accumulation in the human liver seems to be a crucial mechanism in the pathogenesis and the progression of non-alcoholic fatty liver disease (NAFLD). We aimed to evaluate gene expression of different fatty acid (FA) metabolism-related genes in morbidly obese (MO) women with NAFLD. Liver expression of key genes related to de novo FA synthesis (LXRα, SREBP1c, ACC1, FAS), FA uptake and transport (PPARγ, CD36, FABP4), FA oxidation (PPARα), and inflammation (IL6, TNFα, CRP, PPARδ) were assessed by RT-qPCR in 127 MO women with normal liver histology (NL, n = 13), simple steatosis (SS, n = 47) and non-alcoholic steatohepatitis (NASH, n = 67). Liver FAS mRNA expression was significantly higher in MO NAFLD women with both SS and NASH compared to those with NL (p = 0.003, p = 0.010, respectively). Hepatic IL6 and TNFα mRNA expression was higher in NASH than in SS subjects (p = 0.033, p = 0.050, respectively). Interestingly, LXRα, ACC1 and FAS expression had an inverse relation with the grade of steatosis. These results were confirmed by western blot analysis. In conclusion, our results indicate that lipogenesis seems to be downregulated in advanced stages of SS, suggesting that, in this type of extreme obesity, the deregulation of the lipogenic pathway might be associated with the severity of steatosis. Full article

(This article belongs to the collection Molecular Mechanisms of Human Liver Diseases)

Open AccessArticle Non-Alcoholic Fatty Liver Disease in Children: Focus on Nutritional Interventions

by Min Yang, Sitang Gong, Shui Qing Ye, Beth Lyman, Lanlan Geng, Peiyu Chen and Ding-You Li

Nutrients 2014, 6(11), 4691-4705; doi:10.3390/nu6114691

Received: 5 September 2014 / Revised: 9 October 2014 / Accepted: 14 October 2014 / Published: 28 October 2014

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Abstract

With increasing prevalence of childhood obesity, non-alcoholic fatty liver disease (NAFLD) has emerged as the most common cause of liver disease among children and adolescents in industrialized countries. It is generally recognized that both genetic and environmental risk factors contribute to the pathogenesis

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With increasing prevalence of childhood obesity, non-alcoholic fatty liver disease (NAFLD) has emerged as the most common cause of liver disease among children and adolescents in industrialized countries. It is generally recognized that both genetic and environmental risk factors contribute to the pathogenesis of NAFLD. Recently, there has been a growing body of evidence to implicate altered gut microbiota in the development of NAFLD through the gut-liver axis. The first line of prevention and treatment of NAFLD in children should be intensive lifestyle interventions such as changes in diet and physical activity. Recent advances have been focused on limitation of dietary fructose and supplementation of antioxidants, omega-3 fatty acids, and prebiotics/probiotics. Convincing evidences from both animal models and human studies have shown that reduction of dietary fructose and supplement of vitamin E, omega-3 fatty acids, and prebiotics/probiotics improve NAFLD. Full article

(This article belongs to the Special Issue Nutrition and Liver Disease)

Open AccessArticle Monitoring and Evaluation of Alcoholic Fermentation Processes Using a Chemocapacitor Sensor Array

by Petros Oikonomou, Ioannis Raptis and Merope Sanopoulou

Sensors 2014, 14(9), 16258-16273; doi:10.3390/s140916258

Received: 17 June 2014 / Revised: 2 August 2014 / Accepted: 27 August 2014 / Published: 2 September 2014

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Abstract

The alcoholic fermentation of Savatiano must variety was initiated under laboratory conditions and monitored daily with a gas sensor array without any pre-treatment steps. The sensor array consisted of eight interdigitated chemocapacitors (IDCs) coated with specific polymers. Two batches of fermented must were

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The alcoholic fermentation of Savatiano must variety was initiated under laboratory conditions and monitored daily with a gas sensor array without any pre-treatment steps. The sensor array consisted of eight interdigitated chemocapacitors (IDCs) coated with specific polymers. Two batches of fermented must were tested and also subjected daily to standard chemical analysis. The chemical composition of the two fermenting musts differed from day one of laboratory monitoring (due to different storage conditions of the musts) and due to a deliberate increase of the acetic acid content of one of the musts, during the course of the process, in an effort to spoil the fermenting medium. Sensor array responses to the headspace of the fermenting medium were compared with those obtained either for pure or contaminated samples with controlled concentrations of standard ethanol solutions of impurities. Results of data processing with Principal Component Analysis (PCA), demonstrate that this sensing system could discriminate between a normal and a potential spoiled grape must fermentation process, so this gas sensing system could be potentially applied during wine production as an auxiliary qualitative control instrument. Full article

(This article belongs to the Section Chemical Sensors)

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Open AccessReview Epigenetic Mechanisms Underlying the Link between Non-Alcoholic Fatty Liver Diseases and Nutrition

by Joo Ho Lee, Simonetta Friso and Sang-Woon Choi

Nutrients 2014, 6(8), 3303-3325; doi:10.3390/nu6083303

Received: 9 May 2014 / Revised: 6 August 2014 / Accepted: 7 August 2014 / Published: 21 August 2014

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is defined as a pathologic accumulation of fat in the form of triglycerides (TG) in the liver (steatosis) that is not caused by alcohol. A subgroup of NAFLD patients shows liver cell injury and inflammation coupled with the

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Non-alcoholic fatty liver disease (NAFLD) is defined as a pathologic accumulation of fat in the form of triglycerides (TG) in the liver (steatosis) that is not caused by alcohol. A subgroup of NAFLD patients shows liver cell injury and inflammation coupled with the excessive fat accumulation (steatohepatitis), which is referred to as non-alcoholic steatohepatitis (NASH). Patients with NASH may develop cirrhosis and hepatocellular carcinoma (HCC). NAFLD shares the key features of metabolic syndrome including obesity, hyperlipidemia, hypertension, and insulin resistance. The pathogenesis of NAFLD is multi-factorial, however the oxidative stress seems to plays a major role in the development and progression of the disease. The emerging field of epigenetics provides a new perspective on the pathogenesis of NAFLD. Epigenetics is an inheritable but reversible phenomenon that affects gene expression without altering the DNA sequence and refers to DNA methylation, histone modifications and microRNAs. Epigenetic manipulation through metabolic pathways such as one-carbon metabolism has been proposed as a promising approach to retard the progression of NAFLD. Investigating the epigenetic modifiers in NAFLD may also lead to the development of preventive or therapeutic strategies for NASH-associated complications. Full article

(This article belongs to the Special Issue Nutritional Epigenetics)

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Open AccessReview Molecular Mechanisms and New Treatment Strategies for Non-Alcoholic Steatohepatitis (NASH)

by Akinobu Takaki, Daisuke Kawai and Kazuhide Yamamoto

Int. J. Mol. Sci. 2014, 15(5), 7352-7379; doi:10.3390/ijms15057352

Received: 1 March 2014 / Revised: 28 March 2014 / Accepted: 10 April 2014 / Published: 29 April 2014

Cited by 45 | Viewed by 3661 | PDF Full-text (3081 KB) | HTML Full-text | XML Full-text

Abstract

Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD), in which most patients exhibit non-progressive, non-alcoholic fatty liver (NAFL) attributable to simple steatosis. Multiple hits, including genetic differences, fat accumulation, insulin resistance and intestinal microbiota changes, account for the

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Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD), in which most patients exhibit non-progressive, non-alcoholic fatty liver (NAFL) attributable to simple steatosis. Multiple hits, including genetic differences, fat accumulation, insulin resistance and intestinal microbiota changes, account for the progression of NASH. NAFLD is strongly associated with obesity, which induces adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level, which in turn induces hepatic steatosis, inflammation and fibrosis. Among these factors, gut microbiota are acknowledged as having an important role in initiating this multifactorial disease. Oxidative stress is considered to be a key contributor in the progression from NAFL to NASH. Macrophage infiltration is apparent in NAFL and NASH, while T-cell infiltration is apparent in NASH. Although several clinical trials have shown that antioxidative therapy with vitamin E can effectively control hepatitis pathology in the short term, the long-term effects remain obscure and have often proved to be ineffective in many other diseases. Several long-term antioxidant protocols have failed to reduce mortality. New treatment modalities that incorporate current understanding of NAFLD molecular pathogenesis must be considered. Full article

(This article belongs to the collection Molecular Mechanisms of Human Liver Diseases)

Open AccessArticle Fatty Acid Elongation in Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma

by Sonja M. Kessler, Yvette Simon, Katja Gemperlein, Kathrin Gianmoena, Cristina Cadenas, Vincent Zimmer, Juliane Pokorny, Ahmad Barghash, Volkhard Helms, Nico van Rooijen, Rainer M. Bohle, Frank Lammert, Jan G. Hengstler, Rolf Mueller, Johannes Haybaeck and Alexandra K. Kiemer

Int. J. Mol. Sci. 2014, 15(4), 5762-5773; doi:10.3390/ijms15045762

Received: 27 February 2014 / Revised: 17 March 2014 / Accepted: 21 March 2014 / Published: 4 April 2014

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Abstract

Non-alcoholic steatohepatitis (NASH) represents a risk factor for the development of hepatocellular carcinoma (HCC) and is characterized by quantitative and qualitative changes in hepatic lipids. Since elongation of fatty acids from C16 to C18 has recently been reported to promote both hepatic lipid

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Non-alcoholic steatohepatitis (NASH) represents a risk factor for the development of hepatocellular carcinoma (HCC) and is characterized by quantitative and qualitative changes in hepatic lipids. Since elongation of fatty acids from C16 to C18 has recently been reported to promote both hepatic lipid accumulation and inflammation we aimed to investigate whether a frequently used mouse NASH model reflects this clinically relevant feature and whether C16 to C18 elongation can be observed in HCC development. Feeding mice a methionine and choline deficient diet to model NASH not only increased total hepatic fatty acids and cholesterol, but also distinctly elevated the C18/C16 ratio, which was not changed in a model of simple steatosis (ob/ob mice). Depletion of Kupffer cells abrogated both quantitative and qualitative methionine-and-choline deficient (MCD)-induced alterations in hepatic lipids. Interestingly, mimicking inflammatory events in early hepatocarcinogenesis by diethylnitrosamine-induced carcinogenesis (48 h) increased hepatic lipids and the C18/C16 ratio. Analyses of human liver samples from patients with NASH or NASH-related HCC showed an elevated expression of the elongase ELOVL6, which is responsible for the elongation of C16 fatty acids. Taken together, our findings suggest a detrimental role of an altered fatty acid pattern in the progression of NASH-related liver disease. Full article

(This article belongs to the collection Molecular Mechanisms of Human Liver Diseases)

Open AccessArticle The Impacts of Obesity and Metabolic Abnormality on Carotid Intima-Media Thickness and Non-Alcoholic Fatty Liver Disease in Children from an Inland Chinese City

by Xiao-Yue Wang, Xiang-Hua Zhang, Chao Hua Yao, Hong-Hui Zhu and Liang Zhang

J. Clin. Med. 2014, 3(1), 323-333; doi:10.3390/jcm3010323

Received: 9 January 2014 / Revised: 18 February 2014 / Accepted: 24 February 2014 / Published: 20 March 2014

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Abstract

The Chinese inland, where low child obesity and overweight rates were reported in earlier studies, has recently experienced rapid economy changes. This may impact children’s health. In the present study, we investigated the obesity rate, metabolic health status, and their impacts on carotid

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The Chinese inland, where low child obesity and overweight rates were reported in earlier studies, has recently experienced rapid economy changes. This may impact children’s health. In the present study, we investigated the obesity rate, metabolic health status, and their impacts on carotid intima-media thickness (IMT) and non-alcoholic fatty liver disease (NAFLD) among children from Yueyang, an inland city of China. We found that the obesity rate was about 5% for both 7- and 11-year olds. Overweightness rates were 9.5% and 11.5% for the 7- and 11-year olds, respectively. Clinical and laboratory examinations revealed significant differences among different weight groups in the 11-year old volunteers, which were absent in the 7-year olds. Further statistical analysis showed that: age, BMI, blood pressure, triglyceride level, and metabolic abnormality were positively correlated to carotid IMT; triglyceride level, obesity, male, and the number of metabolic abnormalities were independent risk factors for NAFLD in these children. Our study suggests that: childhood overweightness and obesity are now epidemic in Yueyang, which have contributed to increased carotid IMT and may also increased NAFLD incidents; and serum triglyceride level is a critical factor in the development of childhood NAFLD. Thus, childhood metabolic health warrants further vigorous research in the inland of China. Full article

(This article belongs to the Special Issue Obesity, Diabetes and Metabolic Syndrome)

Open AccessReview Multiple Hits, Including Oxidative Stress, as Pathogenesis and Treatment Target in Non-Alcoholic Steatohepatitis (NASH)

by Akinobu Takaki, Daisuke Kawai and Kazuhide Yamamoto

Int. J. Mol. Sci. 2013, 14(10), 20704-20728; doi:10.3390/ijms141020704

Received: 30 August 2013 / Revised: 18 September 2013 / Accepted: 29 September 2013 / Published: 15 October 2013

Cited by 66 | Viewed by 3297 | PDF Full-text (590 KB) | HTML Full-text | XML Full-text

Abstract

Multiple parallel hits, including genetic differences, insulin resistance and intestinal microbiota, account for the progression of non-alcoholic steatohepatitis (NASH). Multiple hits induce adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level that subsequently induce hepatic steatosis, inflammation and fibrosis, among

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Multiple parallel hits, including genetic differences, insulin resistance and intestinal microbiota, account for the progression of non-alcoholic steatohepatitis (NASH). Multiple hits induce adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level that subsequently induce hepatic steatosis, inflammation and fibrosis, among which oxidative stress is considered a key contributor to progression from simple fatty liver to NASH. Although several clinical trials have shown that anti-oxidative therapy can effectively control hepatitis activities in the short term, the long-term effect remains obscure. Several trials of long-term anti-oxidant protocols aimed at treating cerebrovascular diseases or cancer development have failed to produce a benefit. This might be explained by the non-selective anti-oxidative properties of these drugs. Molecular hydrogen is an effective antioxidant that reduces only cytotoxic reactive oxygen species (ROS) and several diseases associated with oxidative stress are sensitive to hydrogen. The progress of NASH to hepatocellular carcinoma can be controlled using hydrogen-rich water. Thus, targeting mitochondrial oxidative stress might be a good candidate for NASH treatment. Long term clinical intervention is needed to control this complex lifestyle-related disease. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)

Open AccessReview Immunological Mechanisms in the Pathophysiology of Non-Alcoholic Steatohepatitis

by Luisa Vonghia, Peter Michielsen and Sven Francque

Int. J. Mol. Sci. 2013, 14(10), 19867-19890; doi:10.3390/ijms141019867

Received: 26 August 2013 / Revised: 11 September 2013 / Accepted: 22 September 2013 / Published: 1 October 2013

Cited by 26 | Viewed by 2523 | PDF Full-text (569 KB) | HTML Full-text | XML Full-text

Abstract

Non-alcoholic steatohepatitis (NASH) is characterized by the presence of steatosis, inflammation and hepatocyte injury and constitutes hepatic manifestation of the metabolic syndrome. The pathogenesis of NASH is complex and implicates cross-talk between different metabolically active sites, such as liver and adipose tissue. Obesity

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Non-alcoholic steatohepatitis (NASH) is characterized by the presence of steatosis, inflammation and hepatocyte injury and constitutes hepatic manifestation of the metabolic syndrome. The pathogenesis of NASH is complex and implicates cross-talk between different metabolically active sites, such as liver and adipose tissue. Obesity is considered a chronic low-grade inflammatory state and the liver has been recognized as being an “immunological organ”. The complex role of the immune system in the pathogenesis of NASH is currently raising great interest, also in view of the possible therapeutic potential of immunotherapy in NASH. This review focuses on the disturbances of the cells constituting the innate and adaptive immune system in the liver and in adipose tissue. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)

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Open AccessArticle Relationship between Serum Osteocalcin Levels and Non-Alcoholic Fatty Liver Disease in Adult Males, South China

by Jun-Jie Liu, Yuan-Yuan Chen, Zeng-Nan Mo, Gui-Xiang Tian, Ai-Hua Tan, Yong Gao, Xiao-Bo Yang, Hai-Ying Zhang and Zhi-Xian Li

Int. J. Mol. Sci. 2013, 14(10), 19782-19791; doi:10.3390/ijms141019782

Received: 31 July 2013 / Revised: 20 September 2013 / Accepted: 22 September 2013 / Published: 30 September 2013

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Abstract

AIM: To determine serum osteocalcin levels in South Chinese males with non-alcoholic fatty liver disease (NAFLD) and to examine the relation between serum osteocalcin and NAFLD. METHODS: Data were collected from 1683 men attending the Fangchenggang Area Male Healthy and Examination Survey (FAMHES)

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AIM: To determine serum osteocalcin levels in South Chinese males with non-alcoholic fatty liver disease (NAFLD) and to examine the relation between serum osteocalcin and NAFLD. METHODS: Data were collected from 1683 men attending the Fangchenggang Area Male Healthy and Examination Survey (FAMHES) from September 2009 to December 2009. Serum osteocalcin was measured with electrochemiluminescence immunoassay. An abdominal ultrasonographic examination for all individuals was performed by two experienced ultrasonographers. The associations of serum osteocalcin with NAFLD were evaluated. RESULTS: The levels of serum osteocalcin were lower in 364 NAFLD participants than in 1319 non-NAFLD participants (24.51 ± 1.38 ng/mL vs. 20.81 ± 1.33 ng/mL, p < 0.001). Serum osteocalin level was associated with the scale of NAFLD (r = −0.150, p < 0.01). Serum osteocalin level tended to decrease with the scale of NAFLD. Binary logistic regression analysis showed that decreased ORs for NAFLD were observed from the first to the fourth osteocalcin quartiles. CONCLUSIONS: Our findings suggest that a lower serum osteocalcin level is associated with the presence of NAFLD. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)

Open AccessReview Dietary Omega-3 Fatty Acid Deficiency and High Fructose Intake in the Development of Metabolic Syndrome, Brain Metabolic Abnormalities, and Non-Alcoholic Fatty Liver Disease

by Artemis P. Simopoulos

Nutrients 2013, 5(8), 2901-2923; doi:10.3390/nu5082901

Received: 8 June 2013 / Revised: 24 July 2013 / Accepted: 24 July 2013 / Published: 26 July 2013

Cited by 36 | Viewed by 6662 | PDF Full-text (567 KB) | HTML Full-text | XML Full-text

Abstract

Western diets are characterized by both dietary omega-3 fatty acid deficiency and increased fructose intake. The latter found in high amounts in added sugars such as sucrose and high fructose corn syrup (HFCS). Both a low intake of omega-3 fatty acids or a

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Western diets are characterized by both dietary omega-3 fatty acid deficiency and increased fructose intake. The latter found in high amounts in added sugars such as sucrose and high fructose corn syrup (HFCS). Both a low intake of omega-3 fatty acids or a high fructose intake contribute to metabolic syndrome, liver steatosis or non-alcoholic fatty liver disease (NAFLD), promote brain insulin resistance, and increase the vulnerability to cognitive dysfunction. Insulin resistance is the core perturbation of metabolic syndrome. Multiple cognitive domains are affected by metabolic syndrome in adults and in obese adolescents, with volume losses in the hippocampus and frontal lobe, affecting executive function. Fish oil supplementation maintains proper insulin signaling in the brain, ameliorates NAFLD and decreases the risk to metabolic syndrome suggesting that adequate levels of omega-3 fatty acids in the diet can cope with the metabolic challenges imposed by high fructose intake in Western diets which is of major public health importance. This review presents the current status of the mechanisms involved in the development of the metabolic syndrome, brain insulin resistance, and NAFLD a most promising area of research in Nutrition for the prevention of these conditions, chronic diseases, and improvement of Public Health. Full article

Open AccessReview In Vitro and in Vivo Models of Non-Alcoholic Fatty Liver Disease (NAFLD)

by Giridhar Kanuri and Ina Bergheim

Int. J. Mol. Sci. 2013, 14(6), 11963-11980; doi:10.3390/ijms140611963

Received: 19 March 2013 / Revised: 17 May 2013 / Accepted: 22 May 2013 / Published: 5 June 2013

Cited by 52 | Viewed by 4646 | PDF Full-text (1367 KB) | HTML Full-text | XML Full-text

Abstract

By now, non-alcoholic fatty liver disease (NAFLD) is considered to be among the most common liver diseases world-wide. NAFLD encompasses a broad spectrum of pathological conditions ranging from simple steatosis to steatohepatitis, fibrosis and finally even cirrhosis; however, only a minority of patients

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By now, non-alcoholic fatty liver disease (NAFLD) is considered to be among the most common liver diseases world-wide. NAFLD encompasses a broad spectrum of pathological conditions ranging from simple steatosis to steatohepatitis, fibrosis and finally even cirrhosis; however, only a minority of patients progress to end-stages of the disease, and the course of the disease progression to the later stages seems to be slow, developing progressively over several years. Key risk factors including overweight, insulin resistance, a sedentary life-style and an altered dietary pattern, as well as genetic factors and disturbances of the intestinal barrier function have been identified in recent years. Despite intense research efforts that lead to the identification of these risk factors, knowledge about disease initiation and molecular mechanisms involved in progression is still limited. This review summarizes diet-induced and genetic animal models, as well as cell culture models commonly used in recent years to add to the understanding of the mechanisms involved in NAFLD, also referring to their advantages and disadvantages. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)

Open AccessReview Non-Alcoholic Fatty Liver Disease (NAFLD) and Its Connection with Insulin Resistance, Dyslipidemia, Atherosclerosis and Coronary Heart Disease

by Melania Gaggini, Mariangela Morelli, Emma Buzzigoli, Ralph A. DeFronzo, Elisabetta Bugianesi and Amalia Gastaldelli

Nutrients 2013, 5(5), 1544-1560; doi:10.3390/nu5051544

Received: 25 February 2013 / Revised: 12 April 2013 / Accepted: 16 April 2013 / Published: 10 May 2013

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Abstract

Non-alcoholic fatty liver disease is marked by hepatic fat accumulation not due to alcohol abuse. Several studies have demonstrated that NAFLD is associated with insulin resistance leading to a resistance in the antilipolytic effect of insulin in the adipose tissue with an increase

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Non-alcoholic fatty liver disease is marked by hepatic fat accumulation not due to alcohol abuse. Several studies have demonstrated that NAFLD is associated with insulin resistance leading to a resistance in the antilipolytic effect of insulin in the adipose tissue with an increase of free fatty acids (FFAs). The increase of FFAs induces mitochondrial dysfunction and development of lipotoxicity. Moreover, in subjects with NAFLD, ectopic fat also accumulates as cardiac and pancreatic fat. In this review we analyzed the mechanisms that relate NAFLD with metabolic syndrome and dyslipidemia and its association with the development and progression of cardiovascular disease. Full article

(This article belongs to the Special Issue Dyslipidemia and Obesity)

Open AccessArticle Non-Alcoholic Fatty Liver Disease Is not Related to the Incidence of Diabetic Nephropathy in Type 2 Diabetes

by Yu-Tao Zhan, Chuan Zhang, Li Li, Chun-Shan Bi, Xin Song and Shu-Tian Zhang

Int. J. Mol. Sci. 2012, 13(11), 14698-14706; doi:10.3390/ijms131114698

Received: 29 August 2012 / Revised: 16 October 2012 / Accepted: 1 November 2012 / Published: 12 November 2012

Cited by 5 | Viewed by 2052 | PDF Full-text (214 KB) | HTML Full-text | XML Full-text

Abstract

To analyze the association between non-alcoholic fatty liver disease (NAFLD) and the incidence of diabetic nephropathy in patients with type 2 diabetes, the incidence of diabetic nephropathy was assessed in 413 type 2 diabetic patients, by testing the 24 h urinary albumin excretion

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To analyze the association between non-alcoholic fatty liver disease (NAFLD) and the incidence of diabetic nephropathy in patients with type 2 diabetes, the incidence of diabetic nephropathy was assessed in 413 type 2 diabetic patients, by testing the 24 h urinary albumin excretion rate (UAER). The NAFLD was diagnosed based on patient’s medical history and liver ultrasound. The difference in diabetic nephropathy incidence between patients with and without NAFLD was tested by χ². Multivariate logistic regression analysis was used to assess the factors associated with diabetic nephropathy among type 2 diabetic patients. Total 363 out of 413 type 2 diabetic patients were enrolled in this study. The incidences of NAFLD and diabetic nephropathy in participants were approximately 56% (202/363) and 38% (137/363) respectively, and there was no significant difference in the prevalence of diabetic nephropathy between patients with and without NAFLD (37.1% vs. 38.5%, p = 0.787). The duration of diabetes (odds ratio [OR] 1.065, 95% confidence interval [CI] 1.014–1.120, p = 0.012), waist circumference (OR 1.077, 95% CI 1.040–1.116, p = 0.000), and fasting blood glucose (FBG; OR 1.136, 95% CI 1.023–1.1262, p = 0.017) were significantly associated with diabetic nephropathy, whereas sex, high blood pressure, total cholesterol (TC), triglyceride (TG), and ankle brachial pressure index (ABI) were not significantly associated with the disorder. The present results suggest that NAFLD is not related to the incidence of diabetic nephropathy in type 2 diabetes, but the duration of diabetes, waist circumference, and FBG are important factors for diabetic nephropathy in type 2 diabetes. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

Open AccessArticle Coenzyme Q Metabolism Is Disturbed in High Fat Diet-Induced Non Alcoholic Fatty Liver Disease in Rats

by Elena Bravo, Simonetta Palleschi, Barbara Rossi, Mariarosaria Napolitano, Luca Tiano, Emanuela D’Amore and Kathleen M Botham

Int. J. Mol. Sci. 2012, 13(2), 1644-1657; doi:10.3390/ijms13021644

Received: 3 December 2011 / Revised: 12 January 2012 / Accepted: 29 January 2012 / Published: 2 February 2012

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Abstract

Oxidative stress is believed to be a major contributory factor in the development of non alcoholic fatty liver disease (NAFLD), the most common liver disorder worldwide. In this study, the effects of high fat diet-induced NAFLD on Coenzyme Q (CoQ) metabolism and plasma

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Oxidative stress is believed to be a major contributory factor in the development of non alcoholic fatty liver disease (NAFLD), the most common liver disorder worldwide. In this study, the effects of high fat diet-induced NAFLD on Coenzyme Q (CoQ) metabolism and plasma oxidative stress markers in rats were investigated. Rats were fed a standard low fat diet (control) or a high fat diet (57% metabolizable energy as fat) for 18 weeks. The concentrations of total (reduced + oxidized) CoQ9 were increased by > 2 fold in the plasma of animals fed the high fat diet, while those of total CoQ10 were unchanged. Reduced CoQ levels were raised, but oxidized CoQ levels were not, thus the proportion in the reduced form was increased by about 75%. A higher percentage of plasma CoQ9 as compared to CoQ10 was in the reduced form in both control and high fat fed rats. Plasma protein thiol (SH) levels were decreased in the high fat-fed rats as compared to the control group, but concentrations of lipid hydroperoxides and low density lipoprotein (LDL) conjugated dienes were unchanged. These results indicate that high fat diet-induced NAFLD in rats is associated with altered CoQ metabolism and increased protein, but not lipid, oxidative stress. Full article

(This article belongs to the Special Issue Antioxidants)

Open AccessArticle Is the Demand for Alcoholic Beverages in Developing Countries Sensitive to Price? Evidence from China

by Guoqiang Tian and Feng Liu

Int. J. Environ. Res. Public Health 2011, 8(6), 2124-2131; doi:10.3390/ijerph8062124

Received: 16 May 2011 / Revised: 1 June 2011 / Accepted: 2 June 2011 / Published: 9 June 2011

Cited by 5 | Viewed by 3490 | PDF Full-text (204 KB) | HTML Full-text | XML Full-text

Abstract

Economic literature in developed countries suggests that demand for alcoholic beverages is sensitive to price, with an estimated price elasticity ranging from −0.38 for beer and −0.7 for liquor. However, few studies have been conducted in developing countries. We employ a large individual-level

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Economic literature in developed countries suggests that demand for alcoholic beverages is sensitive to price, with an estimated price elasticity ranging from −0.38 for beer and −0.7 for liquor. However, few studies have been conducted in developing countries. We employ a large individual-level dataset in China to estimate the effects of price on alcohol demand. Using the data from China Health and Nutrition Survey for the years 1993, 1997, 2000, 2004 and 2006, we estimate two-part models of alcohol demand. Results show the price elasticity is virtually zero for beer and only −0.12 for liquor, which is far smaller than those derived from developed countries. Separate regressions by gender reveals the results are mainly driven by men. The central implication of this study is, while alcohol tax increases can raise government revenue, it alone is not an effective policy to reduce alcohol related problems in China. Full article

(This article belongs to the Special Issue Alcohol and Public Health)

Open AccessReview Molecular Basis and Current Treatment for Alcoholic Liver Disease

by Alejandra Miranda-Mendez, Alejandro Lugo-Baruqui and Juan Armendariz-Borunda

Int. J. Environ. Res. Public Health 2010, 7(5), 1872-1888; doi:10.3390/ijerph7051872

Received: 18 February 2010 / Accepted: 5 March 2010 / Published: 27 April 2010

Cited by 27 | Viewed by 7057 | PDF Full-text (408 KB) | HTML Full-text | XML Full-text

Abstract

Alcohol use disorders and alcohol dependency affect millions of individuals worldwide. The impact of these facts lies in the elevated social and economic costs. Alcoholic liver disease is caused by acute and chronic exposure to ethanol which promotes oxidative stress and inflammatory response.

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Alcohol use disorders and alcohol dependency affect millions of individuals worldwide. The impact of these facts lies in the elevated social and economic costs. Alcoholic liver disease is caused by acute and chronic exposure to ethanol which promotes oxidative stress and inflammatory response. Chronic consumption of ethanol implies liver steatosis, which is the first morphological change in the liver, followed by liver fibrosis and cirrhosis. This review comprises a broad approach of alcohol use disorders, and a more specific assessment of the pathophysiologic molecular basis, and genetics, as well as clinical presentation and current modalities of treatment for alcoholic liver disease. Full article

(This article belongs to the Special Issue Alcohol and Public Health)

Open AccessReview Beer and its Non-Alcoholic Compounds: Role in Pancreatic Exocrine Secretion, Alcoholic Pancreatitis and Pancreatic Carcinoma

by Andreas Gerloff, Manfred V. Singer and Peter Feick

Int. J. Environ. Res. Public Health 2010, 7(3), 1093-1104; doi:10.3390/ijerph7031093

Received: 8 February 2010 / Revised: 2 March 2010 / Accepted: 9 March 2010 / Published: 15 March 2010

Cited by 15 | Viewed by 4664 | PDF Full-text (193 KB) | HTML Full-text | XML Full-text

Abstract

: In this article we provide an overview of the newest data concerning the effect of non-alcoholic constituents of alcoholic beverages, especially of beer, on pancreatic secretion, and their possible role in alcoholic pancreatitis and pancreatic carcinoma. The data indicate that non-alcoholic constituents

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: In this article we provide an overview of the newest data concerning the effect of non-alcoholic constituents of alcoholic beverages, especially of beer, on pancreatic secretion, and their possible role in alcoholic pancreatitis and pancreatic carcinoma. The data indicate that non-alcoholic constituents of beer stimulate pancreatic enzyme secretion in humans and rats, at least in part, by direct action on pancreatic acinar cells. Some non-alcoholic compounds of beer, such as quercetin, resveratrol, ellagic acid or catechins, have been shown to be protective against experimentally induced pancreatitis by inhibiting pancreatic secretion, stellate cell activation or by reducing oxidative stress. Quercetin, ellagic acid and resveratrol also show anti-carcinogenic potential in vitro and in vivo. However, beer contains many more non-alcoholic ingredients. Their relevance in beer-induced functional alterations of pancreatic cells leading to pancreatitis and pancreatic cancer in humans needs to be further evaluated. Full article

(This article belongs to the Special Issue Environmental Research on Alcohol: Public Health Perspectives)

Open AccessReview Alcoholic Pancreatitis: Pathogenesis, Incidence and Treatment with Special Reference to the Associated Pain

by Raffaele Pezzilli and Antonio M. Morselli-Labate

Int. J. Environ. Res. Public Health 2009, 6(11), 2763-2782; doi:10.3390/ijerph6112763

Received: 17 September 2009 / Accepted: 2 November 2009 / Published: 4 November 2009

Cited by 7 | Viewed by 6946 | PDF Full-text (328 KB) | HTML Full-text | XML Full-text

Abstract

Alcoholic pancreatitis continues to stir up controversy. One of the most debated points is whether from onset it is a chronic disease or whether it progresses to a chronic form after repeated episodes of acute pancreatitis. Histological studies on patients with alcoholic pancreatitis

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Alcoholic pancreatitis continues to stir up controversy. One of the most debated points is whether from onset it is a chronic disease or whether it progresses to a chronic form after repeated episodes of acute pancreatitis. Histological studies on patients with alcoholic pancreatitis have shown that the disease is chronic from onset and that alcoholic acute pancreatitis occurs in a pancreas already damaged by chronic lesions. Genetic factors may also play a role in the pathogenesis of alcoholic disease. The incidence of chronic alcoholic pancreatitis seems to have decreased in the last twenty years. Finally, recent therapeutic studies which have shown medical or surgical approaches capable of reducing the pain episodes in chronic pancreatitis patients will be described. Full article

(This article belongs to the Special Issue Alcohol and Public Health)

Open AccessArticle Relationship between Dietary Beef, Fat, and Pork and Alcoholic Cirrhosis

by Francis Stephen Bridges

Int. J. Environ. Res. Public Health 2009, 6(9), 2417-2425; doi:10.3390/ijerph6092417

Received: 21 August 2009 / Accepted: 9 September 2009 / Published: 10 September 2009

Cited by 2 | Viewed by 6479 | PDF Full-text (148 KB) | HTML Full-text | XML Full-text

Abstract

Nanji and French [1] investigated the relationship between per-caput consumption of total fat, beef, and pork and for alcohol consumption and rates of mortality for cirrhosis for 16 countries for 1965. The present study reports significant and positive associations for 1996 and 2003

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Nanji and French [1] investigated the relationship between per-caput consumption of total fat, beef, and pork and for alcohol consumption and rates of mortality for cirrhosis for 16 countries for 1965. The present study reports significant and positive associations for 1996 and 2003 between the following: alcohol consumption and cirrhosis mortality, pork consumption and cirrhosis mortality, the product of alcohol and pork consumption and the product of alcohol and fat consumption. These supportive associations may represent a relationship between the risk of alcoholic cirrhosis and some heretofore unknown dietary or environmental factor related to conditions of pork or fat consumption. Limitations of the study design are discussed. Full article

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