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Special Issue "Non-Alcoholic Fatty Liver Disease Research"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology".

Deadline for manuscript submissions: closed (30 August 2013)

Special Issue Editor

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

Special Issue Information

Dear Colleagues,

Non-alcoholic fatty liver disease (NAFLD) is one of most common chronic liver disease worldwide. The close relationship with epidemic obesity and metabolic syndrome, and the potential progression towards end-stage liver diseases, such as cirrhosis and HCC, makes of NAFLD an emerging global health problem. The assessment of the multifaceted histological/biochemical pattern that characterizes NAFLD and the comprehension of possible complex pathogenetic events/factors involved in the step-by-step manifestation of the specific traits that define this disease are an exciting challenge. New discoveries in this field are, in fact, the optimal start-point to design novel efficient diagnostic and therapeutic approaches for NAFLD.
We invite investigators to contribute original research articles as well as review articles that will stimulate the continuing efforts to understand the pathogenesis of NAFLD and its impact on disease management.
Potential topics could include, but are not limited to:

  • Role of epigenetics and genetics in the development of NAFLD
  • Cellular and molecular networks involved in NAFLD development and its progression towards liver fibrosis and cancer
  • Relationships between obesity/metabolic syndrome and NAFLD: the role of gut
  • In vitro and in vivo animal models that mimic human NAFLD
  • Diagnostic approaches and novel potential “omics” biomarkers
  • Therapeutic interventions in NAFLD development and progression

Dr. Anna Alisi
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF.


Keywords

  • NAFLD pathogenesis
  • NAFLD-related HCC
  • genetic background
  • epigenetics
  • NAFLD experimental models
  • microRNAs
  • metabolomics
  • Targeted-theraphy

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Published Papers (20 papers)

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Research

Jump to: Review

Open AccessArticle Evaluation of Hepatic Tissue Blood Flow Using Xenon Computed Tomography with Fibrosis Progression in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis C
Int. J. Mol. Sci. 2014, 15(1), 1026-1039; doi:10.3390/ijms15011026
Received: 6 November 2013 / Revised: 24 December 2013 / Accepted: 27 December 2013 / Published: 14 January 2014
Cited by 1 | PDF Full-text (1510 KB) | HTML Full-text | XML Full-text
Abstract
Aims: The present study evaluated the utility of xenon computed tomography (Xe-CT) as a noninvasive diagnostic procedure for the measurement of hepatic tissue blood flow (TBF) in patients with nonalcoholic fatty liver disease (NAFLD) or chronic hepatitis C (CH-C). Methods: Xe-CT was [...] Read more.
Aims: The present study evaluated the utility of xenon computed tomography (Xe-CT) as a noninvasive diagnostic procedure for the measurement of hepatic tissue blood flow (TBF) in patients with nonalcoholic fatty liver disease (NAFLD) or chronic hepatitis C (CH-C). Methods: Xe-CT was performed in 93 patients with NAFLD and in 109 patients with CH-C. Subjects were classified into one of three groups, based on fibrosis stage: group 1, no bridging fibrosis; group 2, bridging fibrosis; and group 3, liver cirrhosis. Correlations between hepatic TBFs in each fibrosis stage were examined. Results: In group 1, portal venous TBF (PVTBF), hepatic arterial (HATBF), and total hepatic TBF (THTBF) were significantly lower in patients with in nonalcoholic steatohepatitis (NASH) than in those with CH-C (p < 0.001, p < 0.05, p < 0.001, respectively). In group 2, PVTBF and THTBF were significantly lower in patients with in NASH than in those with CH-C (p < 0.001, p < 0.05, respectively). In group 3, hepatic TBFs were not significantly different when comparing patients with NASH and those with CH-C. Conclusions: PVTBF decreased due to fat infiltration. Therefore, hemodynamic changes occur relatively earlier in NAFLD than in CH-C. Patients with NASH should be monitored carefully for portal hypertensive complications in the early fibrosis stage. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
Open AccessArticle EZH2 Down-Regulation Exacerbates Lipid Accumulation and Inflammation in in Vitro and in Vivo NAFLD
Int. J. Mol. Sci. 2013, 14(12), 24154-24168; doi:10.3390/ijms141224154
Received: 30 August 2013 / Revised: 2 December 2013 / Accepted: 3 December 2013 / Published: 12 December 2013
Cited by 11 | PDF Full-text (4946 KB) | HTML Full-text | XML Full-text
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent, chronic liver diseases, worldwide. It is a multifactorial disease caused by complex interactions between genetic, epigenetic and environmental factors. Recently, several microRNAs, some of which epigenetically regulated, have been found to [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent, chronic liver diseases, worldwide. It is a multifactorial disease caused by complex interactions between genetic, epigenetic and environmental factors. Recently, several microRNAs, some of which epigenetically regulated, have been found to be up- and/or down-regulated during NAFLD development. However, in NAFLD, the essential role of the Polycomb Group protein Enhancer of Zeste Homolog 2 (EZH2), which controls the epigenetic silencing of specific genes and/or microRNAs by trimethylating Lys27 on histone H3, still remains unknown. In this study, we demonstrate that the nuclear expression/activity of the EZH2 protein is down-regulated both in livers from NAFLD rats and in the free fatty acid-treated HepG2. The drop in EZH2 is inversely correlated with: (i) lipid accumulation; (ii) the expression of pro-inflammatory markers including TNF-α and TGF-β; and (iii) the expression of miR-200b and miR-155. Consistently, the pharmacological inhibition of EZH2 by 3-Deazaneplanocin A (DZNep) significantly reduces EZH2 expression/activity, while it increases lipid accumulation, inflammatory molecules and microRNAs. In conclusion, the results of this study suggest that the defective activity of EZH2 can enhance the NAFLD development by favouring steatosis and the de-repression of the inflammatory genes and that of specific microRNAs. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
Open AccessArticle p27 Is a Critical Prognostic Biomarker in Non-Alcoholic Steatohepatitis-Related Hepatocellular Carcinoma
Int. J. Mol. Sci. 2013, 14(12), 23499-23515; doi:10.3390/ijms141223499
Received: 4 September 2013 / Revised: 24 October 2013 / Accepted: 12 November 2013 / Published: 29 November 2013
Cited by 6 | PDF Full-text (377 KB) | HTML Full-text | XML Full-text
Abstract
Non-alcoholic steatohepatitis (NASH) is a recently identified chronic liver disease, which progresses to liver cirrhosis and hepatocellular carcinoma (HCC). As the number of patients studied to date has been limited, clinically useful prognostic biomarkers of NASH-related HCC have not been available. In [...] Read more.
Non-alcoholic steatohepatitis (NASH) is a recently identified chronic liver disease, which progresses to liver cirrhosis and hepatocellular carcinoma (HCC). As the number of patients studied to date has been limited, clinically useful prognostic biomarkers of NASH-related HCC have not been available. In this study, we investigated the status of a cell-cycle regulator, p27, in NASH-related HCC. p27 has been regarded as a prognostic factor in various types of cancer patients. A total of 22 cases with NASH-related HCC were analyzed for p27 protein expression, and phosphorylation at threonine 157 (T157) and serine 10 (S10) by immunohistochemical analysis. The correlation of p27 with tumor characteristics, disease-free survival (DFS), and overall survival was analyzed. p27 expression was decreased in 13 HCCs (59%), and was significantly correlated with enlarged tumor size (p = 0.01) and increased cell proliferation (p < 0.01). Phospho-p27 at T157 and S10 was detected in four (18%) and seven (32%) cases, respectively, and patients positive for phospho-p27 (S10) showed reduced DFS (hazard ratio 7.623, p = 0.016) by univariate analysis. Further studies with more patients are required to verify the usefulness of p27 as a biomarker for predicting tumor recurrence in NASH patients. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
Figures

Open AccessArticle Glycosyltransferase GLT8D2 Positively Regulates ApoB100 Protein Expression in Hepatocytes
Int. J. Mol. Sci. 2013, 14(11), 21435-21446; doi:10.3390/ijms141121435
Received: 18 July 2013 / Revised: 11 September 2013 / Accepted: 12 September 2013 / Published: 29 October 2013
Cited by 4 | PDF Full-text (372 KB) | HTML Full-text | XML Full-text
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by triglyceride (TG) accumulation in hepatocytes. Very low density lipoprotein (VLDL) is a major secretory product of the liver that transports endogenously synthesized TG. Disrupted VLDL secretion may contribute to the accumulation of TG in [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is characterized by triglyceride (TG) accumulation in hepatocytes. Very low density lipoprotein (VLDL) is a major secretory product of the liver that transports endogenously synthesized TG. Disrupted VLDL secretion may contribute to the accumulation of TG in hepatocytes. ApoB100 (apolipoprotein B100) is a glycoprotein and an essential protein component of VLDL. Its glycosylation may affect VLDL assembly and secretion. However, which glycosyltransferase catalyzes apoB100 glycosylation is unknown. In this study, we cloned the GLT8D2 (glycosyltransferase 8 domain containing 2) gene from HepG2 cells and generated a series of plasmids for in vitro studies of its molecular functions. We discovered that GLT8D2 was localized in the ER, interacted with apoB100, and positively regulated the levels of apoB100 protein in HepG2 cells. Based on these results, we propose that GLT8D2 is a glycosyltransferase of apoB100 that regulates apoB100 levels in hepatocytes. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
Open AccessArticle Identification of Combined Genetic Determinants of Liver Stiffness within the SREBP1c-PNPLA3 Pathway
Int. J. Mol. Sci. 2013, 14(10), 21153-21166; doi:10.3390/ijms141021153
Received: 27 August 2013 / Revised: 15 October 2013 / Accepted: 16 October 2013 / Published: 22 October 2013
Cited by 8 | PDF Full-text (286 KB) | HTML Full-text | XML Full-text
Abstract
The common PNPLA3 (adiponutrin) variant, p.I148M, was identified as a genetic determinant of liver fibrosis. Since the expression of PNPLA3 is induced by sterol regulatory element binding protein 1c (SREBP1c), we investigate two common SREBP1c variants (rs2297508 and rs11868035) for their association [...] Read more.
The common PNPLA3 (adiponutrin) variant, p.I148M, was identified as a genetic determinant of liver fibrosis. Since the expression of PNPLA3 is induced by sterol regulatory element binding protein 1c (SREBP1c), we investigate two common SREBP1c variants (rs2297508 and rs11868035) for their association with liver stiffness. In 899 individuals (aged 17–83 years, 547 males) with chronic liver diseases, hepatic fibrosis was non-invasively phenotyped by transient elastography (TE). The SREBP1c single nucleotide polymorphisms (SNPs) were genotyped using PCR-based assays with 5'-nuclease and fluorescence detection. The SREBP1c rs11868035 variant affected liver fibrosis significantly (p = 0.029): median TE levels were 7.2, 6.6 and 6.0 kPa in carriers of (TT) (n = 421), (CT) (n = 384) and (CC) (n = 87) genotypes, respectively. Overall, the SREBP1c SNP was associated with low TE levels (5.0–8.0 kPa). Carriers of both PNPLA3 and SREBP1c risk genotypes displayed significantly (p = 0.005) higher median liver stiffness, as compared to patients carrying none of these variants. The common SREBP1c variant may affect early stages of liver fibrosis. Our study supports a role of the SREBP1c-PNPLA3 pathway as a “disease module” that promotes hepatic fibrogenesis. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
Open AccessArticle Combined Taurine, Epigallocatechin Gallate and Genistein Therapy Reduces HSC-T6 Cell Proliferation and Modulates the Expression of Fibrogenic Factors
Int. J. Mol. Sci. 2013, 14(10), 20543-20554; doi:10.3390/ijms141020543
Received: 12 August 2013 / Revised: 20 September 2013 / Accepted: 22 September 2013 / Published: 14 October 2013
Cited by 7 | PDF Full-text (348 KB) | HTML Full-text | XML Full-text
Abstract
Hepatic fibrogenesis involves the activation of hepatic stellate cells (HSCs), which synthesize excess extracellular matrix and contribute to the development of liver fibrosis. In a prior study we tested the effect of combined treatment with taurine, epigallocatechin gallate and genistein on the [...] Read more.
Hepatic fibrogenesis involves the activation of hepatic stellate cells (HSCs), which synthesize excess extracellular matrix and contribute to the development of liver fibrosis. In a prior study we tested the effect of combined treatment with taurine, epigallocatechin gallate and genistein on the development of alcohol-induced liver fibrosis in vitro. In this study, the biological activity of the combination of these molecules was assessed by measuring its effect on cell proliferation, fibrosis-related gene expression, and proteomic expression profiling in the activated HSC cell line, HSC-T6. HSC-T6 cells were incubated with different concentrations of the drug combination taurine, epigallocatechin gallate and genistein. Cell proliferation was evaluated by MTT assay. Transforming growth factor β1 (TGF-β1), collagen type I (Col-I), matrix metalloproteinase-2 (MMP-2), and tissue inhibitor of metalloproteinases 1 and 2 (TIMP-1 and TIMP-2) mRNA were analyzed by semi-quantitative reverse-transcription PCR. Proteomic profiling of HSC-T6 cells was also performed by SELDI-TOF-MS. Combined drug treatment significantly inhibited cell proliferation and TGF-β1, Col-I, TIMP-1 and TIMP-2 mRNA expression in activated HSC-T6 cells, while the expression of MMP-2 mRNA increased. A total of 176 protein m/z peaks were identified. The intensities of 10 protein peaks were downregulated and two protein peaks were upregulated in HSC-T6 cells after combined drug treatment. In conclusion, combined drug treatment with taurine, epigallocatechin gallate and genistein can inhibit HSC proliferation, and impact fibrosis-related gene and protein expression. The antifibrotic effects of this drug combination may be due to its effects on the expression of fibrogenic genes. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
Open AccessArticle Relationship between Serum Osteocalcin Levels and Non-Alcoholic Fatty Liver Disease in Adult Males, South China
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
Cited by 7 | PDF Full-text (201 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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)

Review

Jump to: Research

Open AccessReview Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation
Int. J. Mol. Sci. 2014, 15(5), 8591-8638; doi:10.3390/ijms15058591
Received: 2 February 2014 / Revised: 20 March 2014 / Accepted: 17 April 2014 / Published: 14 May 2014
Cited by 27 | PDF Full-text (886 KB) | HTML Full-text | XML Full-text
Abstract
Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis and inflammation and, in some patients, progressive fibrosis leading to cirrhosis. An understanding of the pathogenesis of NASH is still evolving but current evidence suggests multiple metabolic factors critically disrupt homeostasis and induce an [...] Read more.
Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis and inflammation and, in some patients, progressive fibrosis leading to cirrhosis. An understanding of the pathogenesis of NASH is still evolving but current evidence suggests multiple metabolic factors critically disrupt homeostasis and induce an inflammatory cascade and ensuing fibrosis. The mechanisms underlying these changes and the complex inter-cellular interactions that mediate fibrogenesis are yet to be fully elucidated. Lipotoxicity, in the setting of excess free fatty acids, obesity, and insulin resistance, appears to be the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence contribute to activation of the inflammasome via a variety of intra- and inter-cellular signalling mechanisms leading to fibrosis. Current evidence suggests that periportal components, including the ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the Th17 response may mediate disease progression. This review aims to provide an overview of the pathogenesis of NASH and summarises the evidence pertaining to key mechanisms implicated in the transition from steatosis and inflammation to fibrosis. Currently there are limited treatments for NASH although an increasing understanding of its pathogenesis will likely improve the development and use of interventions in the future. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
Open AccessReview Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease
Int. J. Mol. Sci. 2014, 15(4), 6184-6223; doi:10.3390/ijms15046184
Received: 4 February 2014 / Revised: 27 March 2014 / Accepted: 1 April 2014 / Published: 11 April 2014
Cited by 97 | PDF Full-text (3149 KB) | HTML Full-text | XML Full-text
Abstract
Accumulating evidence indicates that obesity is closely associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Obesity results from an imbalance between food intake and energy expenditure, which leads to [...] Read more.
Accumulating evidence indicates that obesity is closely associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Obesity results from an imbalance between food intake and energy expenditure, which leads to an excessive accumulation of adipose tissue. Adipose tissue is now recognized not only as a main site of storage of excess energy derived from food intake but also as an endocrine organ. The expansion of adipose tissue produces a number of bioactive substances, known as adipocytokines or adipokines, which trigger chronic low-grade inflammation and interact with a range of processes in many different organs. Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases. In this review, we focus on the role of several adipokines associated with obesity and the potential impact on obesity-related metabolic diseases. Multiple lines evidence provides valuable insights into the roles of adipokines in the development of obesity and its metabolic complications. Further research is still required to fully understand the mechanisms underlying the metabolic actions of a few newly identified adipokines. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
Open AccessReview Meta-Omic Platforms to Assist in the Understanding of NAFLD Gut Microbiota Alterations: Tools and Applications
Int. J. Mol. Sci. 2014, 15(1), 684-711; doi:10.3390/ijms15010684
Received: 10 November 2013 / Revised: 29 December 2013 / Accepted: 2 January 2014 / Published: 7 January 2014
Cited by 5 | PDF Full-text (1250 KB) | HTML Full-text | XML Full-text
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide as a result of the increasing prevalence of obesity, starting from early life stages. It is characterized by a spectrum of liver diseases ranging from simple fatty [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide as a result of the increasing prevalence of obesity, starting from early life stages. It is characterized by a spectrum of liver diseases ranging from simple fatty liver (NAFL) to steatohepatitis (NASH), with a possible progression to fibrosis, thus increasing liver-related morbidity and mortality. NAFLD development is driven by the co-action of several risk factors, including obesity and metabolic syndrome, which may be both genetically induced and diet-related. Recently, particular attention has been paid to the gut-liver axis, which may play a physio-pathological role in the onset and progression of the disease. The gut microbiota is intended to act as a bioreactor that can guarantee autonomous metabolic and immunological functions and that can drive functional strategies within the environment of the body in response to external stimuli. The complexity of the gut microbiota suggests that it behaves as an organ. Therefore, the concept of the gut-liver axis must be complemented with the gut-microbiota-liver network due to the high intricacy of the microbiota components and metabolic activities; these activities form the active diet-driven power plant of the host. Such complexity can only be revealed using systems biology, which can integrate clinical phenomics and gut microbiota data. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
Open AccessReview Nonalcoholic Fatty Liver: A Possible New Target for Type 2 Diabetes Prevention and Treatment
Int. J. Mol. Sci. 2013, 14(11), 22933-22966; doi:10.3390/ijms141122933
Received: 1 October 2013 / Revised: 30 October 2013 / Accepted: 8 November 2013 / Published: 20 November 2013
Cited by 27 | PDF Full-text (328 KB) | HTML Full-text | XML Full-text
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. Several lines of evidence have indicated a pathogenic role of insulin resistance, and a strong association with type 2 diabetes (T2MD) and metabolic syndrome. Importantly, NAFLD appears to enhance the [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. Several lines of evidence have indicated a pathogenic role of insulin resistance, and a strong association with type 2 diabetes (T2MD) and metabolic syndrome. Importantly, NAFLD appears to enhance the risk for T2MD, as well as worsen glycemic control and cardiovascular disease in diabetic patients. In turn, T2MD may promote NAFLD progression. The opportunity to take into account NAFLD in T2MD prevention and care has stimulated several clinical studies in which antidiabetic drugs, such as metformin, thiazolidinediones, GLP-1 analogues and DPP-4 inhibitors have been evaluated in NAFLD patients. In this review, we provide an overview of preclinical and clinical evidences on the possible efficacy of antidiabetic drugs in NAFLD treatment. Overall, available data suggest that metformin has beneficial effects on body weight reduction and metabolic parameters, with uncertain effects on liver histology, while pioglitazone may improve liver histology. Few data, mostly preclinical, are available on DPP4 inhibitors and GLP-1 analogues. The heterogeneity of these studies and the small number of patients do not allow for firm conclusions about treatment guidelines, and further randomized, controlled studies are needed. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
Open AccessReview Environmental Pollution: A Tangible Risk for NAFLD Pathogenesis
Int. J. Mol. Sci. 2013, 14(11), 22052-22066; doi:10.3390/ijms141122052
Received: 2 September 2013 / Revised: 18 October 2013 / Accepted: 24 October 2013 / Published: 7 November 2013
Cited by 6 | PDF Full-text (427 KB) | HTML Full-text | XML Full-text
Abstract
The liver is crucial for human life, and the health of this organ often mirrors the health of the individual. The liver can be the target of several diseases, the most prevalent of which, as a consequence of development and changes in [...] Read more.
The liver is crucial for human life, and the health of this organ often mirrors the health of the individual. The liver can be the target of several diseases, the most prevalent of which, as a consequence of development and changes in human lifestyles, is the nonalcoholic fatty liver disease (NAFLD). NAFLD is a multifactorial disease that embraces many histo-pathologic conditions and is highly linked to metabolic derangements. Technological progress and industrialization have also had the consequence of releasing pollutants in the environment, for instance pesticides or solvents, as well as by-products of discharge, such as the particulate matter. In the last decade, a growing body of evidence has emerged, shedding light on the potential impact of environmental pollutants on liver health and, in particular, on NAFLD occurrence. These contaminants have a great steatogenic potential and need to be considered as tangible NAFLD risk factors. There is an urgent need for a deeper comprehension of their molecular mechanisms of action, as well as for new lines of intervention to reduce their worldwide diffusion. This review wishes to sensitize the community to the effects of several environmental pollutants on liver health. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
Open AccessReview Rodent Models of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis
Int. J. Mol. Sci. 2013, 14(11), 21833-21857; doi:10.3390/ijms141121833
Received: 27 August 2013 / Revised: 14 October 2013 / Accepted: 21 October 2013 / Published: 4 November 2013
Cited by 11 | PDF Full-text (353 KB) | HTML Full-text | XML Full-text
Abstract
Research in nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), has been limited by the availability of suitable models for this disease. A number of rodent models have been described in which the relevant liver pathology develops in an appropriate metabolic [...] Read more.
Research in nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), has been limited by the availability of suitable models for this disease. A number of rodent models have been described in which the relevant liver pathology develops in an appropriate metabolic context. These models are promising tools for researchers investigating one of the key issues of NASH: not so much why steatosis occurs, but what causes the transition from simple steatosis to the inflammatory, progressive fibrosing condition of steatohepatitis. The different rodent models can be classified into two large groups. The first includes models in which the disease is acquired after dietary or pharmacological manipulation, and the second, genetically modified models in which liver disease develops spontaneously. To date, no single rodent model has encompassed the full spectrum of human disease progression, but individual models can imitate particular characteristics of human disease. Therefore, it is important that researchers choose the appropriate rodent models. The purpose of the present review is to discuss the metabolic abnormalities present in the currently available rodent models of NAFLD, summarizing the strengths and weaknesses of the established models and the key findings that have furthered our understanding of the disease’s pathogenesis. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
Open AccessReview Lessons from Mouse Models of High-Fat Diet-Induced NAFLD
Int. J. Mol. Sci. 2013, 14(11), 21240-21257; doi:10.3390/ijms141121240
Received: 30 August 2013 / Revised: 6 October 2013 / Accepted: 12 October 2013 / Published: 24 October 2013
Cited by 20 | PDF Full-text (455 KB) | HTML Full-text | XML Full-text
Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses a clinicopathologic spectrum of diseases ranging from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), the more aggressive form of fatty liver disease that may progress to cirrhosis and cirrhosis-related complications, including hepatocellular carcinoma. The prevalence of [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) encompasses a clinicopathologic spectrum of diseases ranging from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), the more aggressive form of fatty liver disease that may progress to cirrhosis and cirrhosis-related complications, including hepatocellular carcinoma. The prevalence of NAFLD, including NASH, is also increasing in parallel with the growing epidemics of obesity and diabetes. However, the causal relationships between obesity and/or diabetes and NASH or liver tumorigenesis have not yet been clearly elucidated. Animal models of NAFLD/NASH provide crucial information, not only for elucidating the pathogenesis of NAFLD/NASH, but also for examining therapeutic effects of various agents. A high-fat diet is widely used to produce hepatic steatosis and NASH in experimental animals. Several studies, including our own, have shown that long-term high-fat diet loading, which can induce obesity and insulin resistance, can also induce NASH and liver tumorigenesis in C57BL/6J mice. In this article, we discuss the pathophysiology of and treatment strategies for NAFLD and subsequent NAFLD-related complications such as NASH and liver tumorigenesis, mainly based on lessons learned from mouse models of high-fat diet-induced NAFLD/NASH. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
Open AccessReview Multiple Hits, Including Oxidative Stress, as Pathogenesis and Treatment Target in Non-Alcoholic Steatohepatitis (NASH)
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 38 | 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, [...] Read more.
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 Role of Hepatic Progenitor Cells in Nonalcoholic Fatty Liver Disease Development: Cellular Cross-Talks and Molecular Networks
Int. J. Mol. Sci. 2013, 14(10), 20112-20130; doi:10.3390/ijms141020112
Received: 6 August 2013 / Revised: 18 September 2013 / Accepted: 18 September 2013 / Published: 9 October 2013
Cited by 14 | PDF Full-text (1007 KB) | HTML Full-text | XML Full-text
Abstract
Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases ranging from simple fatty liver to nonalcoholic steatohepatitis, (NASH) which may progress to cirrhosis and hepatocellular carcinoma. NASH has been independently correlated with atherosclerosis progression and cardiovascular risk. NASH development is characterized [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases ranging from simple fatty liver to nonalcoholic steatohepatitis, (NASH) which may progress to cirrhosis and hepatocellular carcinoma. NASH has been independently correlated with atherosclerosis progression and cardiovascular risk. NASH development is characterized by intricate interactions between resident and recruited cells that enable liver damage progression. The increasing general agreement is that the cross-talk between hepatocytes, hepatic stellate cells (HSCs) and macrophages in NAFLD has a main role in the derangement of lipid homeostasis, insulin resistance, danger recognition, immune tolerance response and fibrogenesis. Moreover, several evidences have suggested that hepatic stem/progenitor cell (HPCs) activation is a component of the adaptive response of the liver to oxidative stress in NAFLD. HPC activation determines the appearance of a ductular reaction. In NASH, ductular reaction is independently correlated with progressive portal fibrosis raising the possibility of a periportal fibrogenetic pathway for fibrogenesis that is parallel to the deposition of subsinusoidal collagen in zone 3 by HSCs. Recent evidences indicated that adipokines, a class of circulating factors, have a key role in the cross-talk among HSCs, HPCs and liver macrophages. This review will be focused on cellular cross-talk and the relative molecular networks which are at the base of NASH progression and fibrosis. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
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Open AccessReview Development of Nonalcoholic Hepatopathy: Contributions of Oxidative Stress and Advanced Glycation End Products
Int. J. Mol. Sci. 2013, 14(10), 19846-19866; doi:10.3390/ijms141019846
Received: 24 July 2013 / Revised: 7 September 2013 / Accepted: 10 September 2013 / Published: 1 October 2013
Cited by 13 | PDF Full-text (724 KB) | HTML Full-text | XML Full-text
Abstract
Advanced glycation end products (AGEs) are generated spontaneously in cells; however, under conditions of hyperglycemia and lipid peroxidation, their levels are higher than usual, which contribute to the development of diseases such as the nonalcoholic fatty liver disease (NAFLD). NAFLD is associated [...] Read more.
Advanced glycation end products (AGEs) are generated spontaneously in cells; however, under conditions of hyperglycemia and lipid peroxidation, their levels are higher than usual, which contribute to the development of diseases such as the nonalcoholic fatty liver disease (NAFLD). NAFLD is associated with oxidative stress (OS), which is linked to the transition of steatosis to steatohepatitis due to lipid peroxidation. The AGE-receptor interaction in hepatic stellate cells leads to an increase in reactive oxygen species and enhances the proliferation and activation of these cells, worsening liver fibrosis and disease progression. In this vicious cycle, there is production of (carboxymethyl)lysine, a biomarker for products of advanced glycation and lipid peroxidation, being a shared component between the two pathways. In this review, we aim to compile evidence to support the basic molecular mechanisms of AGEs and OS generation and their influence, independently or combined, on the evolution of NAFLD. The deeper understanding of the interrelations of AGEs + OS may help to elucidate the pathogenic pathways of NAFLD and to devise rational therapeutic interventions for this disease, with an expected positive impact on quality of life of patients. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
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Open AccessReview Immunological Mechanisms in the Pathophysiology of Non-Alcoholic Steatohepatitis
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 20 | 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. [...] Read more.
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 AccessReview In Vitro and in Vivo Models of Non-Alcoholic Fatty Liver Disease (NAFLD)
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 29 | 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 [...] Read more.
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 Dual Role of MicroRNAs in NAFLD
Int. J. Mol. Sci. 2013, 14(4), 8437-8455; doi:10.3390/ijms14048437
Received: 14 March 2013 / Revised: 5 April 2013 / Accepted: 10 April 2013 / Published: 17 April 2013
Cited by 18 | PDF Full-text (385 KB) | HTML Full-text | XML Full-text
Abstract
MicroRNAs are important post-transcriptional regulators in different pathophysiological processes. They typically affect the mRNA stability or translation finally leading to the repression of target gene expression. Notably, it is thought that microRNAs are crucial for regulating gene expression during metabolic-related disorders, such [...] Read more.
MicroRNAs are important post-transcriptional regulators in different pathophysiological processes. They typically affect the mRNA stability or translation finally leading to the repression of target gene expression. Notably, it is thought that microRNAs are crucial for regulating gene expression during metabolic-related disorders, such as nonalcoholic fatty liver disease (NAFLD). Several studies identify specific microRNA expression profiles associated to different histological features of NAFLD, both in animal models and in patients. Therefore, specific assortments of certain microRNAs could have enormous diagnostic potentiality. In addition, microRNAs have also emerged as possible therapeutic targets for the treatment of NAFLD-related liver damage. In this review, we discuss the experimental evidence about microRNAs both as potential non-invasive early diagnostic markers and as novel therapeutic targets in NAFLD and its more severe liver complications. Full article
(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)
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