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Special Issue "Nutrition and Non-alcoholic Fatty Liver Disease"

A special issue of Nutrients (ISSN 2072-6643).

Deadline for manuscript submissions: closed (15 July 2017)

Special Issue Editors

Guest Editor
Prof. Valerio Nobili

1. Bambino Gesu Children Hospital, Rome, Italy
2. University "La Sapienza", Rome, Italy
E-Mail
Phone: +390668592212
Interests: fatty liver, metabolic syndrome, nutrients intake and gut-liver diseases
Guest Editor
Dr. Anna Alisi

Liver Research Unit, Laboratory of Liver Diseases (Padiglione Giovanni Paolo II piano-2), Bambino Gesu' Children Hospital P.le S Onofrio, 4 00165 Rome, Italy
E-Mail

Special Issue Information

Dear Colleagues,

We are experiencing a worldwide epidemic of obesity, which is associated with different comorbidities, such as non-alcoholic fatty liver disease (NAFLD), which is currently considered the most common hepatopathy worldwide.

The purpose of this Special Issue, “Nutrition and Non-alcoholic Fatty Liver Disease”, is to provide an overview of the role of different nutrients and dietary models on the development, treatment, prevention, and reversal of NAFLD. A high-calorie diet, particularly rich in saturated fatty acids and cholesterol, sugary drinks with high fructose content, increases visceral adiposity inducing the accumulation of lipids in the hepatocytes and triggers other systemic and tissue specific responses driving the progression of liver damage. These events could be exacerbated by a genetic predisposition. In this context, the reduction of caloric intake, obtained with lifestyle interventions or with dietary supplements (i.e., omega-3 fatty acids, vitamins, probiotics) may contribute to reverse metabolic derangement and liver damage occurring in NAFLD.

The topics covered should include: i) epidemiology of NAFLD and the role nutrition as risk factor; ii) the interaction of nutrition with genetics; iii) the role of breastfeeding; iv) the role of gut microbiota; and v) nutritional programs that can be used to treat or prevent NAFLD; omics approaches to study nutrigenomics in NAFLD.

Prof. Valerio Nobili
Dr. Anna Alisi
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Non-alcoholic fatty liver disease
  • Caloric intake
  • Macronutrients
  • Micronutrients
  • Gene Variants
  • Gut Microbiota
  • Breastfeeding
  • Omega-3 fatty acids
  • Probiotics
  • Vitamins
  • Omics
  • Experimental Models

Published Papers (23 papers)

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Research

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Open AccessArticle Nutritional Profile and Dietary Patterns of Lebanese Non-Alcoholic Fatty Liver Disease Patients: A Case-Control Study
Nutrients 2017, 9(11), 1245; https://doi.org/10.3390/nu9111245
Received: 25 August 2017 / Revised: 3 November 2017 / Accepted: 9 November 2017 / Published: 14 November 2017
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered the most common liver disease in the world. Dietary habits have a significant impact on the biological and physical profile of patients and increase the risk of NAFLD. The overall pattern of diet intake is more
[...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is considered the most common liver disease in the world. Dietary habits have a significant impact on the biological and physical profile of patients and increase the risk of NAFLD. The overall pattern of diet intake is more associated with health outcomes than nutrients. The aim of this study was to evaluate the nutritional profile and the dietary patterns of Lebanese NAFLD patients and compare it with controls. During this study; 112 NAFLD Lebanese adult patients (55 men and 57 women); and 110 controls (44 men and 66 women) were recruited. Dietary intake was evaluated by two 24-h recalls and a semi-quantitative 90-item food frequency questionnaire. Dietary patterns were determined by factor analysis. Results from the study demonstrated that 40% of cases belonged to the high fruit group as compared to 30% following a high meat; fast food dietary pattern. Both groups increased the odds of NAFLD by four-fold (p < 0.05). The traditional diet decreases the odds by 33% after adjustment with the covariables. The high fruit diet group was, as with the high meat, fast food dietary pattern, the main potential risk factor for NAFLD in Lebanese patients. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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Open AccessArticle Qualitative and Quantitative Evaluation of Dietary Intake in Patients with Non-Alcoholic Steatohepatitis
Nutrients 2017, 9(10), 1074; https://doi.org/10.3390/nu9101074
Received: 17 July 2017 / Revised: 23 September 2017 / Accepted: 26 September 2017 / Published: 28 September 2017
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Abstract
There are very few reports about the intake of nutrients for the development or progression of non-alcoholic steatohepatitis (NASH). The aim of this study was to identify the dietary habits and the nutrient intake in patients with NASH, in comparison to chronic hepatitis
[...] Read more.
There are very few reports about the intake of nutrients for the development or progression of non-alcoholic steatohepatitis (NASH). The aim of this study was to identify the dietary habits and the nutrient intake in patients with NASH, in comparison to chronic hepatitis C (HCV)-related patients. We prospectively evaluated the intake of macronutrients and micronutrients in 124 NAFLD and 162 HCV patients, compared to 2326 subjects as a control group. We noticed major differences in macro- and micronutrients intakes in NASH and HCV patients compared to controls. Proteins, carbohydrate (glucose, fructose, sucrose, maltose and amide), saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), folic acid, vitamin A and C (p < 0.0001), and thiamine (p < 0.0003) ingestion was found to be higher in patients with NASH, while total lipids, polyunsaturated fatty acid (PUFA), riboflavin and vitamin B6 daily intake were lower compared to controls (p < 0.0001). Similarly, NASH patients had significantly reduced carbohydrate intake (p < 0.0001) and an increased intake of calcium (p < 0.0001) compared to HCV positive patients. Finally, we showed in NASH males an increase in the intake of SFA, PUFA, soluble carbohydrates (p < 0.0001) and a decrease in the amount of fiber (p < 0.0001) compared to control males. In NASH female population, we showed an increase of daily total calories, SFA, MUFA, soluble carbohydrates, starch and vitamin D ingested (p < 0.0001) with a reduction of fibers and calcium (p < 0.0001) compared to control females. This study showed how NASH patients’ diets, in both male and females, is affected by a profound alteration in macro- and micronutrients intake. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
Open AccessArticle Combination of Hypertension Along with a High Fat and Cholesterol Diet Induces Severe Hepatic Inflammation in Rats via a Signaling Network Comprising NF-κB, MAPK, and Nrf2 Pathways
Nutrients 2017, 9(9), 1018; https://doi.org/10.3390/nu9091018
Received: 13 July 2017 / Revised: 29 August 2017 / Accepted: 11 September 2017 / Published: 14 September 2017
Cited by 1 | PDF Full-text (2659 KB) | HTML Full-text | XML Full-text
Abstract
Populations with essential hypertension have a high risk of nonalcoholic steatohepatitis (NASH). In this study, we investigated the mechanism that underlies the progression of hypertension-associated NASH by comparing differences in the development of high fat and cholesterol (HFC) diet-induced NASH among three strains
[...] Read more.
Populations with essential hypertension have a high risk of nonalcoholic steatohepatitis (NASH). In this study, we investigated the mechanism that underlies the progression of hypertension-associated NASH by comparing differences in the development of high fat and cholesterol (HFC) diet-induced NASH among three strains of rats, i.e., two hypertensive strains comprising spontaneously hypertensive rats and the stroke-prone spontaneously hypertensive 5/Dmcr, and the original Wistar Kyoto rats as the normotensive control. We investigated histopathological changes and molecular signals related to inflammation in the liver after feeding with the HFC diet for 8 weeks. The diet induced severe lobular inflammation and fibrosis in the livers of the hypertensive rats, whereas it only caused mild steatohepatitis in the normotensive rats. An increased activation of proinflammatory signaling (transforming growth factor-β1/mitogen-activated protein kinases pathway) was observed in the hypertensive strains fed with the HFC diet. In addition, the HFC diet suppressed the nuclear factor erythroid 2-related factor 2 pathway in the hypertensive rats and led to lower increases in the hepatic expression of heme oxygenase-1, which has anti-oxidative and anti-inflammatory activities. In conclusion, these signaling pathways might play crucial roles in the development of hypertension-associated NASH. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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Open AccessArticle Short-Term Intake of a Fructose-, Fat- and Cholesterol-Rich Diet Causes Hepatic Steatosis in Mice: Effect of Antibiotic Treatment
Nutrients 2017, 9(9), 1013; https://doi.org/10.3390/nu9091013
Received: 14 June 2017 / Revised: 31 August 2017 / Accepted: 11 September 2017 / Published: 14 September 2017
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Abstract
Intestinal microbiota and barrier functions seem to play an important role in the development of non-alcoholic fatty liver disease (NAFLD). However, whether these changes are an early event in the development of NAFLD or are primarily associated with later stages of the disease,
[...] Read more.
Intestinal microbiota and barrier functions seem to play an important role in the development of non-alcoholic fatty liver disease (NAFLD). However, whether these changes are an early event in the development of NAFLD or are primarily associated with later stages of the disease, has not yet been clarified. Using a pair-feeding model, we determined the effects of a short-term intake of a fat-, fructose- and cholesterol-rich diet (FFC) on the development of early hepatic steatosis and markers of intestinal barrier function in mice treated with and without non-resorbable antibiotics (AB). For four days, C57BL/6J mice were either pair-fed a control diet or a FFC diet ± AB (92 mg/kg body weight (BW) polymyxin B and 216 mg/kg BW neomycin). Hepatic steatosis and markers of inflammation, lipidperoxidation and intestinal barrier function were assessed. Lipid accumulation and early signs of inflammation found in the livers of FFC-fed mice were markedly attenuated in FFC + AB-fed animals. In FFC-fed mice the development of NAFLD was associated with a significant loss of tight junction proteins and an induction of matrix metalloproteinase-13 in the upper parts of the small intestine as well as significantly higher portal endotoxin levels and an induction of dependent signaling cascades in the liver. As expected, portal endotoxin levels and the expression of dependent signaling cascades in liver tissue were almost at the level of controls in FFC + AB-fed mice. However, FFC + AB-fed mice were also protected from the loss of zonula occludens-1 and partially of occludin protein in small intestine. Our data suggest that the development of early diet-induced hepatic steatosis in mice at least in part results from alterations of intestinal barrier function. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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Open AccessArticle Effects of Oral Administration of Silymarin in a Juvenile Murine Model of Non-alcoholic Steatohepatitis
Nutrients 2017, 9(9), 1006; https://doi.org/10.3390/nu9091006
Received: 12 July 2017 / Revised: 7 September 2017 / Accepted: 9 September 2017 / Published: 12 September 2017
Cited by 1 | PDF Full-text (4474 KB) | HTML Full-text | XML Full-text
Abstract
The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in adolescents is challenging the global care system. No therapeutic strategies have been defined so far, and changes in the lifestyle remain the only alternative. In this study, we assessed the protective effects of
[...] Read more.
The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in adolescents is challenging the global care system. No therapeutic strategies have been defined so far, and changes in the lifestyle remain the only alternative. In this study, we assessed the protective effects of silymarin in a juvenile non-alcoholic steatohepatitis (NASH) model and the in vitro effects on fat-laden human hepatocytes. C57Bl/6 mice were exposed to HFHC diet immediately after weaning. After eight weeks, animals showed histological signs of NASH. Silymarin was added to the HFHC diet, the treatment continued for additional 12 weeks and the effects on BMI, hepatomegaly, visceral fat, lipid profile, transaminases, HOMA-IR, steatosis, inflammation, fibrosis, oxidative stress, and apoptosis were determined. The switch from HFHC to control diet was used to mimic life style changes. In vitro experiments were performed in parallel in human hepatocytes. HFHC diet supplemented with silymarin showed a significant improvement in glycemia, visceral fat, lipid profile, and liver fibrosis. Moreover, it reduced (both in vitro and in vivo) ALT, hepatic inflammation, oxidative stress, and apoptosis. Lifestyle changes restored the control group parameters. The data presented show the beneficial effects of the oral administration of silymarin in the absence of changes in the dietary habits in a juvenile model of NASH. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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Open AccessArticle Type 1 Diabetes and Non-Alcoholic Fatty Liver Disease: When Should We Be Concerned? A Nationwide Study in Brazil
Nutrients 2017, 9(8), 878; https://doi.org/10.3390/nu9080878
Received: 15 July 2017 / Revised: 3 August 2017 / Accepted: 5 August 2017 / Published: 15 August 2017
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Abstract
Obesity is increasing worldwide, affecting even patients with type 1 diabetes (T1D). A higher prevalence of associated comorbidities is expected, such as non-alcoholic fatty liver disease (NAFLD). This paper reports a cross-sectional multicenter study on a population with T1D (n = 1662),
[...] Read more.
Obesity is increasing worldwide, affecting even patients with type 1 diabetes (T1D). A higher prevalence of associated comorbidities is expected, such as non-alcoholic fatty liver disease (NAFLD). This paper reports a cross-sectional multicenter study on a population with T1D (n = 1662), which aimed to evaluate the prevalence of metabolic syndrome (MS), a known risk factor for NAFLD, and to investigate predisposing factors associated with MS, as well as factors associated with elevated alanine aminotransferase (ALT), as it correlates to liver fat content. Patients were from 14 public clinics of 10 cities from all geographical regions of Brazil. A high prevalence of MS was found, especially among adults (32.3%), and this was related to age, female gender, acid uric levels, and the presence of acanthosis nigricans. ALT above the normal range was associated with triglyceride levels (especially above 129.5 mg/dL), serum uric acid, age, male gender, HbA1c, and non-Caucasian ethnicity. Patients with T1D, metabolic syndrome, and the aforementioned factors may be at a higher risk of NAFLD and should be referred to ultrasound for NAFLD evaluation. Further studies are necessary to establish the prevalence of NAFLD in individuals with T1D and to determine the disease’s progression in these patients. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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Open AccessArticle Serum Iron:Ferritin Ratio Predicts Healthy Body Composition and Reduced Risk of Severe Fatty Liver in Young Adult Women
Nutrients 2017, 9(8), 833; https://doi.org/10.3390/nu9080833
Received: 28 June 2017 / Revised: 21 July 2017 / Accepted: 1 August 2017 / Published: 4 August 2017
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Abstract
Dysregulated iron metabolism is associated with altered body composition and nonalcoholic fatty liver disease (NAFLD); however, mechanisms underlying this association remain undefined. We investigated this association in 117 women. Middle-aged women (≥45 years old (y)) were heavier and had lower serum iron, higher
[...] Read more.
Dysregulated iron metabolism is associated with altered body composition and nonalcoholic fatty liver disease (NAFLD); however, mechanisms underlying this association remain undefined. We investigated this association in 117 women. Middle-aged women (≥45 years old (y)) were heavier and had lower serum iron, higher serum hepcidin, ferritin, and severe NAFLD incidence than young adult women (<45 y). Age-adjusted linear regression analysis revealed that young adult women with the highest serum iron:ferritin ratio (Tertile 3) had a 5.08-unit increased percentage of muscle mass [β = 5.08 (1.48–8.68), p < 0.001] and a 1.21-unit decreased percentage visceral fat mass [β = −1.21 (−2.03 to −0.39), p < 0.001] compared with those with the lowest serum iron:ferritin ratio (Tertile 1; reference). The iron:ferritin dietary pattern, characterized by high consumption of beef, lamb, dairy products, fruits, and whole grains, and low consumption of refined carbohydrates (rice, noodles, and bread and pastries), and deep- and stir-fried foods, predicted a 90% [odds ratio: 0.10, 95% confidence interval: 0.02–0.47, p < 0.001] reduced risk of mild vs. moderate and severe NAFLD in young adult women. Our findings suggest that the serum iron:ferritin ratio more accurately predicts body composition and reduced risk of severe fatty liver progression in young adult women compared to middle-aged women. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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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
Nutrients 2017, 9(7), 774; https://doi.org/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
[...] Read more.
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
Nutrients 2017, 9(7), 766; https://doi.org/10.3390/nu9070766
Received: 16 May 2017 / Revised: 19 June 2017 / Accepted: 12 July 2017 / Published: 18 July 2017
Cited by 2 | PDF Full-text (3985 KB) | HTML Full-text | XML Full-text
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
[...] Read more.
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 A Branched-Chain Amino Acid-Related Metabolic Signature Characterizes Obese Adolescents with Non-Alcoholic Fatty Liver Disease
Nutrients 2017, 9(7), 642; https://doi.org/10.3390/nu9070642
Received: 1 May 2017 / Revised: 2 June 2017 / Accepted: 19 June 2017 / Published: 22 June 2017
Cited by 4 | PDF Full-text (1806 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Dysregulation of several metabolite pathways, including branched-chain amino acids (BCAAs), are associated with Non-Alcoholic Fatty Liver Disease (NAFLD) and insulin resistance in adults, while studies in youth reported conflicting results. We explored whether, independently of obesity and insulin resistance, obese adolescents with NAFLD
[...] Read more.
Dysregulation of several metabolite pathways, including branched-chain amino acids (BCAAs), are associated with Non-Alcoholic Fatty Liver Disease (NAFLD) and insulin resistance in adults, while studies in youth reported conflicting results. We explored whether, independently of obesity and insulin resistance, obese adolescents with NAFLD display a metabolomic signature consistent with disturbances in amino acid and lipid metabolism. A total of 180 plasma metabolites were measured by a targeted metabolomic approach in 78 obese adolescents with (n = 30) or without (n = 48) NAFLD assessed by magnetic resonance imaging (MRI). All subjects underwent an oral glucose tolerance test and subsets of patients underwent a two-step hyperinsulinemic-euglycemic clamp and/or a second MRI after a 2.2 ± 0.8-year follow-up. Adolescents with NAFLD had higher plasma levels of valine (p = 0.02), isoleucine (p = 0.03), tryptophan (p = 0.02), and lysine (p = 0.02) after adjustment for confounding factors. Circulating BCAAs were negatively correlated with peripheral and hepatic insulin sensitivity. Furthermore, higher baseline valine levels predicted an increase in hepatic fat content (HFF) at follow-up (p = 0.01). These results indicate that a dysregulation of BCAA metabolism characterizes obese adolescents with NAFLD independently of obesity and insulin resistance and predict an increase in hepatic fat content over time. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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Open AccessArticle Urinary Metabolomics in Pediatric Obesity and NAFLD Identifies Metabolic Pathways/Metabolites Related to Dietary Habits and Gut-Liver Axis Perturbations
Nutrients 2017, 9(5), 485; https://doi.org/10.3390/nu9050485
Received: 2 April 2017 / Revised: 28 April 2017 / Accepted: 6 May 2017 / Published: 11 May 2017
Cited by 4 | PDF Full-text (2170 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
To get insight into still elusive pathomechanisms of pediatric obesity and non-alcoholic fatty liver disease (NAFLD) we explored the interplay among GC-MS studied urinary metabolomic signature, gut liver axis (GLA) abnormalities, and food preferences (Kid-Med). Intestinal permeability (IP), small intestinal bacterial overgrowth (SIBO),
[...] Read more.
To get insight into still elusive pathomechanisms of pediatric obesity and non-alcoholic fatty liver disease (NAFLD) we explored the interplay among GC-MS studied urinary metabolomic signature, gut liver axis (GLA) abnormalities, and food preferences (Kid-Med). Intestinal permeability (IP), small intestinal bacterial overgrowth (SIBO), and homeostatic model assessment-insulin resistance were investigated in forty children (mean age 9.8 years) categorized as normal weight (NW) or obese (body mass index <85th or >95th percentile, respectively) ± ultrasonographic bright liver and hypertransaminasemia (NAFLD). SIBO was increased in all obese children (p = 0.0022), IP preferentially in those with NAFLD (p = 0.0002). The partial least-square discriminant analysis of urinary metabolome correctly allocated children based on their obesity, NAFLD, visceral fat, pathological IP and SIBO. Compared to NW, obese children had (1) higher levels of glucose/1-methylhistidine, the latter more markedly in NAFLD patients; and (2) lower levels of xylitol, phenyl acetic acid and hydroquinone, the latter especially in children without NAFLD. The metabolic pathways of BCAA and/or their metabolites correlated with excess of visceral fat centimeters (leucine/oxo-valerate), and more deranged IP and SIBO (valine metabolites). Urinary metabolome analysis contributes to define a metabolic fingerprint of pediatric obesity and related NAFLD, by identifying metabolic pathways/metabolites reflecting typical obesity dietary habits and GLA perturbations. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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Open AccessArticle Homocysteine Induces Hepatic Steatosis Involving ER Stress Response in High Methionine Diet-Fed Mice
Nutrients 2017, 9(4), 346; https://doi.org/10.3390/nu9040346
Received: 14 February 2017 / Revised: 16 March 2017 / Accepted: 28 March 2017 / Published: 1 April 2017
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Abstract
Elevated circulating homocysteine (Hcy) has been proposed to be associated with non-alcoholic fatty liver disease (NAFLD). It is also reported that Hcy causes protein misfolding in the endoplasmic reticulum (ER). In this study, we used a high methionine diet (HMD)-fed mouse model and
[...] Read more.
Elevated circulating homocysteine (Hcy) has been proposed to be associated with non-alcoholic fatty liver disease (NAFLD). It is also reported that Hcy causes protein misfolding in the endoplasmic reticulum (ER). In this study, we used a high methionine diet (HMD)-fed mouse model and cultured primary hepatocytes to investigate the effects of Hcy on hepatic lipids metabolism. C57BL/6J mice received either standard chow diet (CT, n = 10) or diet supplemented with 2% methionine (MET, n = 10) for 16 weeks. In in vitro experiments, cultured mouse primary hepatocytes were treated with Hcy, or Hcy combined with 4-phenylbutyric acid (4-PBA), or tunicamycin (TM), respectively. HMD-fed mice exhibited a mild increase in plasma Hcy level. There was no significant difference of body weight gain between the two groups. Nevertheless, HMD feeding increased epididymal fat/body weight ratio, elevated plasma triglyceride (TG) level, and decreased high-density lipoprotein cholesterol (HDL) level. Similarly, mice on HMD displayed higher liver/body weight ratio, plasma aspartate aminotransferase (AST) and its ratio to alanine aminotransferase (ALT), which was supported by the morphological observations of hepatic triglyceride accumulation in liver tissue as well as primary hepatocytes. Activation of the sterol response element-binding protein 1c (SREBP1c) in Hcy-treated hepatocytes with increased expression of genes involved in hepatic de novo lipogenesis was partially reduced by pretreatment of 4-PBA. Hcy-induced ER stress was also ameliorated by 4-PBA pretreatment, thus demonstrating an important role of Hcy-induced ER stress response in hepatic steatosis. These findings suggest that elevated Hcy was a critical factor in the pathogenesis of NAFLD. Activation of the ER stress response may be involved in Hcy-induced hepatic steatosis. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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Review

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Open AccessFeature PaperReview Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD)
Nutrients 2018, 10(1), 29; https://doi.org/10.3390/nu10010029
Received: 7 November 2017 / Revised: 13 December 2017 / Accepted: 19 December 2017 / Published: 29 December 2017
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Abstract
Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and
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Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true “vitamin A deficiency”, but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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Open AccessReview Non-Alcoholic Fatty Liver Disease and Nutritional Implications: Special Focus on Copper
Nutrients 2017, 9(10), 1137; https://doi.org/10.3390/nu9101137
Received: 26 July 2017 / Revised: 25 September 2017 / Accepted: 8 October 2017 / Published: 18 October 2017
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Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by excess lipids in hepatocytes, due to excessive fatty acid influx from adipose tissue, de novo hepatic lipogenesis, in addition to excessive dietary fat and carbohydrate intake. Chronic hepatic lipid overload induces mitochondrial oxidative stress and
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Non-alcoholic fatty liver disease (NAFLD) is characterized by excess lipids in hepatocytes, due to excessive fatty acid influx from adipose tissue, de novo hepatic lipogenesis, in addition to excessive dietary fat and carbohydrate intake. Chronic hepatic lipid overload induces mitochondrial oxidative stress and cellular damage leading the development of NAFLD into a more severe liver disease condition, non-alcoholic steato-hepatitis (NASH). In turn, this can progress to cirrhosis and hepatocellular carcinoma (HCC). Among others, copper is one of the main bio-metals required for the preponderance of the enzymes involved in physiological redox reactions, which primarily occurs during mitochondrial respiration. Thus, copper homeostasis could be considered a target point for counteracting the progression of NAFLD. Accordingly, many diseases are correlated to unbalanced copper levels and, actually, some clinical trials are examining the use of copper chelating agents. Currently, no pharmacological interventions are approved for NAFLD, but nutritional and lifestyle modifications are always recommended. Fittingly, antioxidant food agents recognized to improve NAFLD and its complications have been described in the literature to bind copper. Therefore, this review describes the role of nutrition in the development and progression of NAFLD with a particular focus on copper and copper-binding antioxidant compounds against NAFLD. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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Open AccessReview Translational Aspects of Diet and Non-Alcoholic Fatty Liver Disease
Nutrients 2017, 9(10), 1077; https://doi.org/10.3390/nu9101077
Received: 5 July 2017 / Revised: 25 September 2017 / Accepted: 26 September 2017 / Published: 28 September 2017
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Abstract
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of diseases ranging from simple steatosis without inflammation or fibrosis to nonalcoholic steatohepatitis (NASH). Despite the strong association between dietary factors and NAFLD, no dietary animal model of NAFLD fully recapitulates the complex metabolic and
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Non-alcoholic fatty liver disease (NAFLD) is a spectrum of diseases ranging from simple steatosis without inflammation or fibrosis to nonalcoholic steatohepatitis (NASH). Despite the strong association between dietary factors and NAFLD, no dietary animal model of NAFLD fully recapitulates the complex metabolic and histological phenotype of the disease, although recent models show promise. Although animal models have significantly contributed to our understanding of human diseases, they have been less successful in accurate translation to predict effective treatment strategies. We discuss strategies to overcome this challenge, in particular the adoption of big data approaches combining clinical phenotype, genomic heterogeneity, transcriptomics, and metabolomics changes to identify the ideal NAFLD animal model for a given scientific question or to test a given drug. We conclude by noting that novel big data approaches may help to bridge the translational gap for selecting dietary models of NAFLD. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
Open AccessReview Animal Models of Nonalcoholic Fatty Liver Disease—A Starter’s Guide
Nutrients 2017, 9(10), 1072; https://doi.org/10.3390/nu9101072
Received: 15 August 2017 / Revised: 13 September 2017 / Accepted: 25 September 2017 / Published: 27 September 2017
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Abstract
Nonalcoholic fatty liver disease (NAFLD) constitutes a major health concern with the increasing incidence of obesity and diabetes in many Western countries, reaching a prevalence of up to 30% in the general population. Animal models have played a vital role in elucidating the
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Nonalcoholic fatty liver disease (NAFLD) constitutes a major health concern with the increasing incidence of obesity and diabetes in many Western countries, reaching a prevalence of up to 30% in the general population. Animal models have played a vital role in elucidating the pathophysiological mechanisms of NAFLD and continue to do so. A myriad of different models exists, each with its advantages and disadvantages. This review presents a brief overview of these models with a particular focus on the basic mechanisms and physical, biochemical and histological phenotype. Both nutritional and chemically induced, as well as genetic models are examined, including models combining different approaches. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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Open AccessReview Isocaloric Dietary Changes and Non-Alcoholic Fatty Liver Disease in High Cardiometabolic Risk Individuals
Nutrients 2017, 9(10), 1065; https://doi.org/10.3390/nu9101065
Received: 3 August 2017 / Revised: 28 August 2017 / Accepted: 21 September 2017 / Published: 26 September 2017
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Abstract
Non-alcoholic fatty liver disease (NAFLD) incorporates an extensive spectrum of histologic liver abnormalities, varying from simple triglyceride accumulation in hepatocytes non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), and it is the most frequent chronic liver disease in the industrialized world. Beyond liver
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Non-alcoholic fatty liver disease (NAFLD) incorporates an extensive spectrum of histologic liver abnormalities, varying from simple triglyceride accumulation in hepatocytes non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), and it is the most frequent chronic liver disease in the industrialized world. Beyond liver related complications such as cirrhosis and hepatocellular carcinoma, NAFLD is also an emerging risk factor for type 2 diabetes and cardiovascular disease. Currently, lifestyle intervention including strategies to reduce body weight and to increase regular physical activity represents the mainstay of NAFLD management. Total caloric intake plays a very important role in both the development and the treatment of NAFLD; however, apart from the caloric restriction alone, modifying the quality of the diet and modulating either the macro- or micronutrient composition can also markedly affect the clinical evolution of NAFLD, offering a more realistic and feasible treatment alternative. The aim of the present review is to summarize currently available evidence from randomized controlled trials on the effects of different nutrients including carbohydrates, lipids, protein and other dietary components, in isocaloric conditions, on NAFLD in people at high cardiometabolic risk. We also describe the plausible mechanisms by which different dietary components could modulate liver fat content. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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Open AccessReview Mediterranean Diet and Multi-Ingredient-Based Interventions for the Management of Non-Alcoholic Fatty Liver Disease
Nutrients 2017, 9(10), 1052; https://doi.org/10.3390/nu9101052
Received: 25 July 2017 / Revised: 1 September 2017 / Accepted: 11 September 2017 / Published: 22 September 2017
Cited by 3 | PDF Full-text (358 KB) | HTML Full-text | XML Full-text
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprises a wide spectrum of hepatic disorders, from simple steatosis to hepatic necro-inflammation leading to non-alcoholic steatohepatitis (NASH). Although the prevalence of these multifactorial pathologies is continuously increasing in the population, there is still not an established methodology
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Non-alcoholic fatty liver disease (NAFLD) comprises a wide spectrum of hepatic disorders, from simple steatosis to hepatic necro-inflammation leading to non-alcoholic steatohepatitis (NASH). Although the prevalence of these multifactorial pathologies is continuously increasing in the population, there is still not an established methodology for their treatment other than weight loss and a change in lifestyle habits, such as a hypocaloric diet and physical exercise. In this framework, there is increasing evidence that several food bioactives and dietary patterns are effective for reversing and preventing the onset of these pathologies. Some studies have claimed that better responses are obtained when treatments are performed under a multifaceted approach, using different bioactive compounds that act against complementary targets. Thus, in this work, current strategies for treating NAFLD and NASH based on multi-ingredient-based supplements or the Mediterranean diet, a dietary pattern rich in bioactive compounds, are reviewed. Furthermore, the usefulness of omics techniques to design effective multi-ingredient nutritional interventions and to predict and monitor their response against these disorders is also discussed. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
Open AccessReview Vitamin D Supplementation and Non-Alcoholic Fatty Liver Disease: Present and Future
Nutrients 2017, 9(9), 1015; https://doi.org/10.3390/nu9091015
Received: 20 August 2017 / Revised: 4 September 2017 / Accepted: 11 September 2017 / Published: 14 September 2017
Cited by 3 | PDF Full-text (209 KB) | HTML Full-text | XML Full-text
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic disease throughout the Western world and is recognized as the main cause of cryptogenic cirrhosis; however, the identification of an effective therapy for NAFLD is still a major challenge. Vitamin D deficiency
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Non-alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic disease throughout the Western world and is recognized as the main cause of cryptogenic cirrhosis; however, the identification of an effective therapy for NAFLD is still a major challenge. Vitamin D deficiency is a wide-spread condition which reaches epidemic proportions in industrialized countries, mainly in relation to current lifestyle and limited dietary sources. Epidemiological studies point towards an association between hypovitaminosis D and the presence of NAFLD and steatohepatitis (NASH), independently of confounders such as obesity and insulin resistance. Furthermore, several pieces of experimental data have shown the anti-fibrotic, anti-inflammatory and insulin-sensitizing properties exerted by vitamin D on hepatic cells. However, results from trials evaluating the effects of oral vitamin D supplementation on liver damage in NAFLD and NASH are controversial. The aim of this review is to give an overview of the evidence currently available from clinical trials and to discuss possible shortcomings and new strategies to be considered in future investigations. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
Open AccessReview Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease
Nutrients 2017, 9(9), 981; https://doi.org/10.3390/nu9090981
Received: 28 July 2017 / Revised: 25 August 2017 / Accepted: 4 September 2017 / Published: 6 September 2017
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Abstract
Increased fructose consumption has been suggested to contribute to non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and insulin resistance, but a causal role of fructose in these metabolic diseases remains debated. Mechanistically, hepatic fructose metabolism yields precursors that can be used for gluconeogenesis and
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Increased fructose consumption has been suggested to contribute to non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and insulin resistance, but a causal role of fructose in these metabolic diseases remains debated. Mechanistically, hepatic fructose metabolism yields precursors that can be used for gluconeogenesis and de novo lipogenesis (DNL). Fructose-derived precursors also act as nutritional regulators of the transcription factors, including ChREBP and SREBP1c, that regulate the expression of hepatic gluconeogenesis and DNL genes. In support of these mechanisms, fructose intake increases hepatic gluconeogenesis and DNL and raises plasma glucose and triglyceride levels in humans. However, epidemiological and fructose-intervention studies have had inconclusive results with respect to liver fat, and there is currently no good human evidence that fructose, when consumed in isocaloric amounts, causes more liver fat accumulation than other energy-dense nutrients. In this review, we aim to provide an overview of the seemingly contradicting literature on fructose and NAFLD. We outline fructose physiology, the mechanisms that link fructose to NAFLD, and the available evidence from human studies. From this framework, we conclude that the cellular mechanisms underlying hepatic fructose metabolism will likely reveal novel targets for the treatment of NAFLD, dyslipidemia, and hepatic insulin resistance. Finally, fructose-containing sugars are a major source of excess calories, suggesting that a reduction of their intake has potential for the prevention of NAFLD and other obesity-related diseases. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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Open AccessReview Dietary Composition Independent of Weight Loss in the Management of Non-Alcoholic Fatty Liver Disease
Nutrients 2017, 9(8), 800; https://doi.org/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 AccessReview Toxic AGE (TAGE) Theory for the Pathophysiology of the Onset/Progression of NAFLD and ALD
Nutrients 2017, 9(6), 634; https://doi.org/10.3390/nu9060634
Received: 2 May 2017 / Revised: 6 June 2017 / Accepted: 16 June 2017 / Published: 20 June 2017
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Abstract
Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are among the most common causes of chronic liver diseases in the westernized world. NAFLD and ALD are frequently accompanied by extrahepatic complications, including hepatocellular carcinoma and cardiovascular diseases, which have a negative
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Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are among the most common causes of chronic liver diseases in the westernized world. NAFLD and ALD are frequently accompanied by extrahepatic complications, including hepatocellular carcinoma and cardiovascular diseases, which have a negative impact on patient survival. The chronic ingestion of an excessive daily diet containing sugar/high-fructose corn syrup increases the level of the fructose/glucose metabolite, glyceraldehyde (GA), while the chronic consumption of an excessive number of alcoholic beverages increases the level of the alcohol metabolite, acetaldehyde (AA) in the liver. GA and AA are known to react non-enzymatically with the ε- or α-amino groups of proteins, thereby generating advanced glycation end-products (AGEs, GA-AGEs, and AA-AGEs, respectively) in vivo. The interaction between GA-AGEs and the receptor for AGEs (RAGE) alters intracellular signaling, gene expression, and the release of pro-inflammatory molecules and also elicits the production of reactive oxygen species by human hepatocytes and hepatic stellate cells, all of which may contribute to the pathological changes associated with chronic liver diseases. We herein discuss the pathophysiological roles of GA-AGEs and AA-AGEs (toxic AGEs, TAGE) and a related novel theory for preventing the onset/progression of NAFLD and ALD. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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Open AccessReview Nonalcoholic Fatty Liver Disease and Insulin Resistance: New Insights and Potential New Treatments
Nutrients 2017, 9(4), 387; https://doi.org/10.3390/nu9040387
Received: 14 March 2017 / Revised: 6 April 2017 / Accepted: 10 April 2017 / Published: 14 April 2017
Cited by 9 | PDF Full-text (1474 KB) | HTML Full-text | XML Full-text
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders worldwide. It is associated with clinical states such as obesity, insulin resistance, and type 2 diabetes, and covers a wide range of liver changes, ranging from simple steatosis to
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Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders worldwide. It is associated with clinical states such as obesity, insulin resistance, and type 2 diabetes, and covers a wide range of liver changes, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. Metabolic disorders, such as lipid accumulation, insulin resistance, and inflammation, have been implicated in the pathogenesis of NAFLD, but the underlying mechanisms, including those that drive disease progression, are not fully understood. Both innate and recruited immune cells mediate the development of insulin resistance and NASH. Therefore, modifying the polarization of resident and recruited macrophage/Kupffer cells is expected to lead to new therapeutic strategies in NAFLD. Oxidative stress is also pivotal for the progression of NASH, which has generated interest in carotenoids as potent micronutrient antioxidants in the treatment of NAFLD. In addition to their antioxidative function, carotenoids regulate macrophage/Kupffer cell polarization and thereby prevent NASH progression. In this review, we summarize the molecular mechanisms involved in the pathogenesis of NAFLD, including macrophage/Kupffer cell polarization, and disturbed hepatic function in NAFLD. We also discuss dietary antioxidants, such as β-cryptoxanthin and astaxanthin, that may be effective in the prevention or treatment of NAFLD. Full article
(This article belongs to the Special Issue Nutrition and Non-alcoholic Fatty Liver Disease)
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