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Special Issue "Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease"

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

Deadline for manuscript submissions: 31 July 2019

Special Issue Editors

Guest Editor
Prof. Dr. Amalia Gastaldelli

Institute of Clinical Physiology National Research Council, Pisa 56100, Italy
Website | E-Mail
Interests: pharmacokinetics; nutrition and metabolism
Guest Editor
Prof. Dr. Silvia Fargion

Ospedale Maggiore Policlinico Milano, Internal Medicine and Metabolic Diseases, Milan, Italy
Website | E-Mail

Special Issue Information

Dear Colleagues,

The worldwide obesity epidemic has increased the incidence of metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). NAFLD prevalence is now estimated to be 25% of the world population and is the most common cause of liver transplantation. Although several mechanisms have been hypothesized, further research is needed to understand genetic modifiers, natural history, and the molecular pathogenesis of NAFLD, as well as the biological mechanisms by which NAFLD progresses to non-alcoholic steatohepatitis (NASH), influences the risk of hepatocarcinoma (HCC) and extra-hepatic diseases. Furthermore, the impact of environment (e.g., exposure to bacteria, virus or pollutants) on the onset of NAFLD and metabolic abnormalities is becoming evident. 

This Special Issue of IJMS, will cover a selection of original articles and current reviews in the field of “Pathophysiological Molecular Mechanisms of Non-Alcoholic Fatty Liver Disease ".

We invite investigators to contribute either original research articles or review articles focusing on the variety of  mechanisms that either contribute to the onset and worsening of NAFLD in lean vs obese patients, in  type 2 diabetic vs non diabetics subjects and to the development of hepatocellular carcinoma in NASH.

Prof. Dr. Amalia Gastaldelli
Prof. Dr. Silvia Fargion
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind 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 semimonthly 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 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

  • Metabolic vs genetic NAFLD
  • Alterations in lipid synthesis and lipid composition
  • Ectopic fat accumulation, lipotoxicity and lipid mediated cell signaling
  • Inflammation
  • Metabolomics and lipidomics
  • Protein metabolism and sarcopenia
  • NAFLD and virus
  • Gut liver axis, gut microbiota and gut hormones
  • Bile acids
  • Mitochondrial function in NAFLD
  • Energy expenditure and Exercise
  • Food composition and different types of diets
  • Environmental factors that can promote NAFLD
  • Fibrosis in NAFLD
  • Hepatocellular carcinoma in NASH

Published Papers (9 papers)

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Research

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Open AccessArticle
Hepatoprotective Effect of Kombucha Tea in Rodent Model of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis
Int. J. Mol. Sci. 2019, 20(9), 2369; https://doi.org/10.3390/ijms20092369
Received: 1 April 2019 / Revised: 3 May 2019 / Accepted: 8 May 2019 / Published: 13 May 2019
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Abstract
Kombucha tea (KT) has emerged as a substance that protects the liver from damage; however, its mechanisms of action on the fatty liver remain unclear. Therefore, we investigated the potential role of KT and its underlying mechanisms on nonalcoholic fatty liver disease (NAFLD). [...] Read more.
Kombucha tea (KT) has emerged as a substance that protects the liver from damage; however, its mechanisms of action on the fatty liver remain unclear. Therefore, we investigated the potential role of KT and its underlying mechanisms on nonalcoholic fatty liver disease (NAFLD). db/db mice that were fed methionine/choline-deficient (MCD) diets for seven weeks were treated for vehicle (M + V) or KT (M + K) and fed with MCD for four additional weeks. Histomorphological injury and increased levels of liver enzymes and lipids were evident in the M + V group, whereas these symptoms were ameliorated in the M + K group. The M + K group had more proliferating and less apoptotic hepatocytic cells than the M + V group. Lipid uptake and lipogenesis significantly decreased, and free fatty acid (FFA) oxidation increased in the M + K, when compared with the M + V group. With the reduction of hedgehog signaling, inflammation and fibrosis also declined in the M + K group. Palmitate (PA) treatment increased the accumulation of lipid droplets and decreased the viability of primary hepatocytes, whereas KT suppressed PA-induced damage in these cells by enhancing intracellular lipid disposal. These results suggest that KT protects hepatocytes from lipid toxicity by influencing the lipid metabolism, and it attenuates inflammation and fibrosis, which contributes to liver restoration in mice with NAFLD. Full article
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Open AccessArticle
Human Multilineage 3D Spheroids as a Model of Liver Steatosis and Fibrosis
Int. J. Mol. Sci. 2019, 20(7), 1629; https://doi.org/10.3390/ijms20071629
Received: 25 February 2019 / Revised: 29 March 2019 / Accepted: 30 March 2019 / Published: 2 April 2019
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Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in western countries. Despite the high prevalence of NAFLD, the underlying biology of the disease progression is not clear, and there are no approved drugs to treat non-alcoholic steatohepatitis (NASH), the most [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in western countries. Despite the high prevalence of NAFLD, the underlying biology of the disease progression is not clear, and there are no approved drugs to treat non-alcoholic steatohepatitis (NASH), the most advanced form of the disease. Thus, there is an urgent need for developing advanced in vitro human cellular systems to study disease mechanisms and drug responses. We attempted to create an organoid system genetically predisposed to NAFLD and to induce steatosis and fibrosis in it by adding free fatty acids. We used multilineage 3D spheroids composed by hepatocytes (HepG2) and hepatic stellate cells (LX-2) with a physiological ratio (24:1). HepG2 and LX-2 cells are homozygotes for the PNPLA3 I148M sequence variant, the strongest genetic determinant of NAFLD. We demonstrate that hepatic stellate cells facilitate the compactness of 3D spheroids. Then, we show that the spheroids develop accumulations of fat and collagen upon exposure to free fatty acids. Finally, this accumulation was rescued by incubating spheroids with liraglutide or elafibranor, drugs that are in clinical trials for the treatment of NASH. In conclusion, we have established a simple, easy to handle, in vitro model of genetically induced NAFLD consisting of multilineage 3D spheroids. This tool may be used to understand molecular mechanisms involved in the early stages of fibrogenesis induced by lipid accumulation. Moreover, it may be used to identify new compounds to treat NASH using high-throughput drug screening. Full article
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Open AccessArticle
Diet-Independent Correlations between Bacteria and Dysfunction of Gut, Adipose Tissue, and Liver: A Comprehensive Microbiota Analysis in Feces and Mucosa of the Ileum and Colon in Obese Mice with NAFLD
Int. J. Mol. Sci. 2019, 20(1), 1; https://doi.org/10.3390/ijms20010001
Received: 6 November 2018 / Revised: 4 December 2018 / Accepted: 15 December 2018 / Published: 20 December 2018
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Abstract
Development of non-alcoholic fatty liver disease (NAFLD) is linked to obesity, adipose tissue inflammation, and gut dysfunction, all of which depend on diet. So far, studies have mainly focused on diet-related fecal microbiota changes, but other compartments may be more informative on host [...] Read more.
Development of non-alcoholic fatty liver disease (NAFLD) is linked to obesity, adipose tissue inflammation, and gut dysfunction, all of which depend on diet. So far, studies have mainly focused on diet-related fecal microbiota changes, but other compartments may be more informative on host health. We present a first systematic analysis of microbiota changes in the ileum and colon using multiple diets and investigating both fecal and mucosal samples. Ldlr−/−.Leiden mice received one of three different energy-dense (ED)-diets (n = 15/group) for 15 weeks. All of the ED diets induced obesity and metabolic risk factors, altered short-chain fatty acids (SCFA), and increased gut permeability and NAFLD to various extents. ED diets reduced the diversity of high-abundant bacteria and increased the diversity of low-abundant bacteria in all of the gut compartments. The ED groups showed highly variable, partially overlapping microbiota compositions that differed significantly from chow. Correlation analyses demonstrated that (1) specific groups of bacteria correlate with metabolic risk factors, organ dysfunction, and NAFLD endpoints, (2) colon mucosa had greater predictive value than other compartments, (3) correlating bacteria differed per compartment, and (4) some bacteria correlated with plasma SCFA levels. In conclusion, this comprehensive microbiota analysis demonstrates correlations between the microbiota and dysfunctions of gut, adipose tissue, and liver, independent of a specific disease-inducing diet. Full article
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Open AccessArticle
Regulation of Leptin Methylation Not via Apoptosis by Melatonin in the Rescue of Chronic Programming Liver Steatosis
Int. J. Mol. Sci. 2018, 19(11), 3565; https://doi.org/10.3390/ijms19113565
Received: 1 October 2018 / Revised: 28 October 2018 / Accepted: 7 November 2018 / Published: 12 November 2018
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Abstract
We examined the mechanisms of chronic liver steatosis after prenatal dexamethasone exposure and whether melatonin rescues adult offspring with liver steatosis. Melatonin rescued prenatal dexamethasone-exposed livers with steatosis in young rats. Sprague-Dawley rats pregnant at gestational day 14–21 were administered with intraperitoneal dexamethasone [...] Read more.
We examined the mechanisms of chronic liver steatosis after prenatal dexamethasone exposure and whether melatonin rescues adult offspring with liver steatosis. Melatonin rescued prenatal dexamethasone-exposed livers with steatosis in young rats. Sprague-Dawley rats pregnant at gestational day 14–21 were administered with intraperitoneal dexamethasone (DEX) or prenatal dexamethasone and melatonin between gestational day 14 and postnatal day ~120 (DEX+MEL). Chronic programming effects in the liver were assessed at day ~120. Liver steatosis increased in the DEX compared with that in the vehicle group and decreased in the DEX+MEL group (p < 0.05), with no changes in cellular apoptosis. Expression of leptin and its receptor decreased in the DEX (p < 0.05) and increased in the DEX+MEL group (p < 0.05), as revealed by RT-PCR and Western blotting. Tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 expression increased in the DEX group compared with that in the vehicle group and decreased in the DEX+MEL group (p < 0.05). Liver DNA methyltransferase activity and leptin methylation increased in the DEX group (p < 0.05) and decreased in the DEX+MEL group (p < 0.05), with no changes in HDAC activity. Thus, prenatal dexamethasone induces liver steatosis at ~120 days via altered leptin expression and liver inflammation without leptin resistance. Melatonin reverses leptin methylation and expression and decreases inflammation and chronic liver steatosis not via apoptosis or histone deacetylation (HDAC). Full article
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Open AccessArticle
Hepatoprotective Effect of Loquat Leaf Flavonoids in PM2.5-Induced Non-Alcoholic Fatty Liver Disease via Regulation of IRs-1/Akt and CYP2E1/JNK Pathways
Int. J. Mol. Sci. 2018, 19(10), 3005; https://doi.org/10.3390/ijms19103005
Received: 29 August 2018 / Revised: 23 September 2018 / Accepted: 26 September 2018 / Published: 1 October 2018
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Abstract
Ambient air particulate matter (PM) represents a class of heterogeneous substances present in polluted air, which contains many harmful components. Exposure to ambient particulate matter in fine rages (PM2.5) is associated with non-alcoholic fatty liver disease (NAFLD). Loquat Leaf possesses pharmacological [...] Read more.
Ambient air particulate matter (PM) represents a class of heterogeneous substances present in polluted air, which contains many harmful components. Exposure to ambient particulate matter in fine rages (PM2.5) is associated with non-alcoholic fatty liver disease (NAFLD). Loquat Leaf possesses pharmacological actions on NAFLD. As the main biological active ingredients, the potential therapeutic role of total flavonoids (TF) isolated from Loquat Leaf in PM2.5-induced NAFLD model remains unclear. The present study was designed to explore the hepatoprotective effect of TF in PM2.5-induced NAFLD mice with its related mechanisms of action. Mice were exposed to PM2.5 to induce NAFLD, and body weight, the ratio of liver to body weight, and blood lipids increased significantly compared with the control group. It was found that TF significantly reduced the above parameters in PM2.5-induced NAFLD mice. TF treatment alleviated oxidative stress by preventing the accumulation of oxidative product malondialdehyde (MDA) and by strengthening the anti-oxidative capacity of superoxide dismutase (SOD). TF was also found to reduce the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity in the PM2.5 group. In addition, TF repaired the PM2.5-induced decline of insulin receptor substrate-1 (IRs-1) and protein kinase B (Akt) phosphorylation. Meanwhile, the data showed TF suppressed the expression of cytochrome P450 2E1(CYP2E1) and the phosphorylation of c-jun N-terminal kinase (JNK) in PM2.5-induced NAFLD. Taken together, these findings show that TF alleviate PM2.5-induced NAFLD via regulation of IRs-1/Akt and CYP2E1/JNK pathways, which may have potential for further development as novel therapeutic agents for NAFLD. Full article
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Review

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Open AccessReview
Cardio-Metabolic Disorders in Non-Alcoholic Fatty Liver Disease
Int. J. Mol. Sci. 2019, 20(9), 2215; https://doi.org/10.3390/ijms20092215
Received: 23 March 2019 / Revised: 19 April 2019 / Accepted: 28 April 2019 / Published: 6 May 2019
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Abstract
With the progressive epidemics of obesity, non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in adults and children. The increasing prevalence and incidence of NAFLD with advanced fibrosis is concerning because patients appear to experience higher [...] Read more.
With the progressive epidemics of obesity, non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in adults and children. The increasing prevalence and incidence of NAFLD with advanced fibrosis is concerning because patients appear to experience higher non-liver-related morbidity and mortality than the general population. Recent clinical evidence suggests that NAFLD is directly associated with an increased risk of cardio-metabolic disorders. This mini review describes briefly the current understanding of the pathogenesis of NAFLD, summarizing the link between NAFLD and cardio-metabolic complications, focusing mainly upon ischemic stroke, type 2 diabetes mellitus (DM), hypertension, chronic kidney disease (CKD) and cardiac arrhythmias. In addition, it describes briefly the current understanding of the pathogenesis of NAFLD. Full article
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Open AccessReview
Pathophysiological, Molecular and Therapeutic Issues of Nonalcoholic Fatty Liver Disease: An Overview
Int. J. Mol. Sci. 2019, 20(8), 1948; https://doi.org/10.3390/ijms20081948
Received: 22 March 2019 / Revised: 18 April 2019 / Accepted: 20 April 2019 / Published: 20 April 2019
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Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) represents the leading cause of liver disease in developed countries but its diffusion is currently also emerging in Asian countries, in South America and in other developing countries. It is progressively becoming one of the main diseases responsible [...] Read more.
Nonalcoholic Fatty Liver Disease (NAFLD) represents the leading cause of liver disease in developed countries but its diffusion is currently also emerging in Asian countries, in South America and in other developing countries. It is progressively becoming one of the main diseases responsible for hepatic insufficiency, hepatocarcinoma and the need for orthotopic liver transplantation. NAFLD is linked with metabolic syndrome in a close and bidirectional relationship. To date, NAFLD is a diagnosis of exclusion, and liver biopsy is the gold standard for diagnosis. NAFLD pathogenesis is complex and multifactorial, mainly involving genetic, metabolic and environmental factors. New concepts are constantly arising in the literature promising new diagnostic and therapeutic tools. One of the challenges will be to better characterize not only NAFLD development but overall NAFLD progression, in order to better identify NAFLD patients at higher risk of metabolic, cardiovascular and neoplastic complications. This review analyses NAFLD epidemiology and the different prevalence of the disease in distinct groups, particularly according to sex, age, body mass index, type 2 diabetes and dyslipidemia. Furthermore, the work expands on the pathophysiology of NAFLD, examining multiple-hit pathogenesis and the role of different factors in hepatic steatosis development and progression: genetics, metabolic factors and insulin resistance, diet, adipose tissue, gut microbiota, iron deposits, bile acids and circadian clock. In conclusion, the current available therapies for NAFLD will be discussed. Full article
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Open AccessReview
Mitogen Activated Protein Kinases in Steatotic and Non-Steatotic Livers Submitted to Ischemia-Reperfusion
Int. J. Mol. Sci. 2019, 20(7), 1785; https://doi.org/10.3390/ijms20071785
Received: 8 March 2019 / Revised: 3 April 2019 / Accepted: 9 April 2019 / Published: 10 April 2019
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Abstract
We analyzed the participation of mitogen-activated protein kinases (MAPKs), namely p38, JNK and ERK 1/2 in steatotic and non-steatotic livers undergoing ischemia-reperfusion (I-R), an unresolved problem in clinical practice. Hepatic steatosis is a major risk factor in liver surgery because these types of [...] Read more.
We analyzed the participation of mitogen-activated protein kinases (MAPKs), namely p38, JNK and ERK 1/2 in steatotic and non-steatotic livers undergoing ischemia-reperfusion (I-R), an unresolved problem in clinical practice. Hepatic steatosis is a major risk factor in liver surgery because these types of liver tolerate poorly to I-R injury. Also, a further increase in the prevalence of steatosis in liver surgery is to be expected. The possible therapies based on MAPK regulation aimed at reducing hepatic I-R injury will be discussed. Moreover, we reviewed the relevance of MAPK in ischemic preconditioning (PC) and evaluated whether MAPK regulators could mimic its benefits. Clinical studies indicated that this surgical strategy could be appropriate for liver surgery in both steatotic and non-steatotic livers undergoing I-R. The data presented herein suggest that further investigations are required to elucidate more extensively the mechanisms by which these kinases work in hepatic I-R. Also, further researchers based in the development of drugs that regulate MAPKs selectively are required before such approaches can be translated into clinical liver surgery. Full article
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Open AccessReview
miRNA Signature in NAFLD: A Turning Point for a Non-Invasive Diagnosis
Int. J. Mol. Sci. 2018, 19(12), 3966; https://doi.org/10.3390/ijms19123966
Received: 8 November 2018 / Revised: 3 December 2018 / Accepted: 6 December 2018 / Published: 10 December 2018
Cited by 3 | PDF Full-text (732 KB) | HTML Full-text | XML Full-text
Abstract
Nonalcoholic fatty liver disease (NAFLD) defines a wide pathological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which may predispose to liver cirrhosis and hepatocellular carcinoma. It represents the leading cause of hepatic damage worldwide. Diagnosis of NASH still requires liver biopsy [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) defines a wide pathological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which may predispose to liver cirrhosis and hepatocellular carcinoma. It represents the leading cause of hepatic damage worldwide. Diagnosis of NASH still requires liver biopsy but due to the high prevalence of NAFLD, this procedure, which is invasive, is not practicable for mass screening. Thus, it is crucial to non-invasively identify NAFLD patients at higher risk of progression to NASH and fibrosis. It has been demonstrated that hepatic fat content and progressive liver damage have a strong heritable component. Therefore, genetic variants associated with NAFLD have been proposed as non-invasive markers to be used in clinical practice. However, genetic variability is not completely explained by these common variants and it is possible that many of the phenotypic differences result from gene-environment interactions. Indeed, NAFLD development and progression is also modulated by epigenetic factors, in particular microRNAs (miRNAs), which control at post-transcriptional level many complementary target mRNAs and whose dysregulation has been shown to have high prognostic and predictive value in NAFLD. The premise of the current review is to discuss the role of miRNAs as pathogenic factors, risk predictors and therapeutic targets in NAFLD. Full article
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