Comparison between metabolic-associated fatty liver disease and nonalcoholic fatty liver disease:From nomenclature to clinical outcomes

As a result of the obesity epidemic,Nonalcoholic fatty liver disease(NAFLD)and its complications have increased among millions of people.Consequently,a group of experts recommended changing the term NAFLD to an inclusive terminology more reflective of the underlying pathogenesis;metabolic-associated fatty liver disease(MAFLD).This new term of MAFLD has its own disease epidemiology and clinical outcomes prompting efforts in studying its differences from NAFLD.This article discusses the rationale behind the nomenclature change,the main differences,and its clinical implications.

Significance of gut microbiota in alcoholic and non-alcoholic fatty liver diseases

Liver-gut communication is vital in fatty liver diseases,and gut microbes are the key regulators in maintaining liver homeostasis.Chronic alcohol abuse and persistent overnutrition create dysbiosis in gut ecology,which can contribute to fatty liver disease.In this review,we discuss the gut microbial compositional changes that occur in alcoholic and nonalcoholic fatty liver diseases and how this gut microbial dysbiosis and its metabolic products are involved in fatty liver disease pathophysiology.We also summarize the new approaches related to gut microbes that might help in the diagnosis and treatment of fatty liver disease.

Non-alcoholic fatty liver disease and thyroid dysfunction:A systematic review

Thyroid hormones are totally involved in the regulation of body weight, lipid metabolism, and insulin resistance. Therefore it is anticipated that thyroid hormones may have a role in the pathogenesis of non alcoholic fatty liver disease(NAFLD) and non alcoholic steatohepatitis(NASH). In this study, we reviewed the current literature on the association between thyroid dysfunction and NAFLD/NASH. A search for English language medical literature reporting an association between thyroid dysfunction and NAFLD/NASH in humans was conducted across PubMed, ISI Web of Science, and Scopus in August, 2013. Out of 140 studies initially identified through the search, 11 relevant articles were included in the final review. Thyroid dysfunctions in the form of overt or subclinical hypothyroidism are prevalent among patients with NAFLD/NASH. Hypothyroidism appears to be an independent risk factor for NAFLD/NASH in some studies; however, other newly published studies failed to find such anassociation. The results of the studies on the role of thyroid abnormalities in NAFLD/NASH are inconsistent, and further research is recommended to determine the relationship between hypothyroidism and NAFLD/NASH and the underlying mechanisms.

Surgically induced weight loss by gastric bypass improves non alcoholic fatty liver disease in morbid obese patients

AIM: To evaluate the effects of surgical weight loss (Roux-en-Y gastric bypass with a modified Fobi-Capella technique) on non alcoholic fatty liver disease in obese patients.

Intestinal virome:An important research direction for alcoholic and nonalcoholic liver diseases

In recent years,the interaction between the gut microflora and liver diseases has attracted much attention.The intestinal microflora is composed of bacteria,archaea,fungi and viruses.There are few studies on the intestinal virome,and whether it has a causal relationship with bacterial changes in the gut is still unclear.However,it is undeniable that the intestinal virome is also a very important portion of the blueprint for the development of liver diseases and the diagnosis and therapeutic modalities in the future.

Pediatric fatty liver disease:Role of ethnicity and genetics

Non-alcoholic fatty liver disease (NAFLD) comprehends a wide range of conditions, encompassing from fatty liver or steatohepatitis with or without fibrosis, to cirrhosis and its complications. NAFLD has become the most common form of liver disease in childhood as its prevalence has more than doubled over the past 20 years, paralleling the increased prevalence of childhood obesity. It currently affects between 3% and 11% of the pediatric population reaching the rate of 46% among overweight and obese children and adolescents. The prevalence of hepatic steatosis varies among different ethnic groups. The ethnic group with the highest prevalence is the Hispanic one followed by the Caucasian and the African-American. This evidence suggests that there is a strong genetic background in the predisposition to fatty liver. In fact, since 2008 several common gene variants have been implicated in the pathogenesis of fatty liver disease. The most important is probably the patatin like phospholipase containing domain 3 gene (PNPLA3) discovered by the Hobbs’ group in 2008. This article reviews the current knowledge regarding the role of ethnicity and genetics in pathogenesis of pediatric fatty liver.

Obese children with fatty liver: Between reality and disease mongering

Following the current epidemic of obesity, the worldwide prevalence of nonalcoholic fatty liver disease(NAFLD)has increased with potential serious health implications. While it is established that in adults NAFLD can progress to end-stage liver disease in many cases, the risk of progression during childhood is less well defined. Since most obese children are not adherent to lifestyle modifications and hypocaloric diets, there is a growing number of studies on pharmacological interventions with the risk of disease mongering, the practice of widening the boundaries of illness in order to expand the markets for treatment. Here, we propose a critical appraisal of the best available evidence about long-term course of pediatric NAFLD and efficacy of treatments other than hypocaloric diet and physical exercise. As a result, the number of NAFLD children with a poor outcome is small in spite of the alarming tones used in some papers; large-scale longitudinal studies with longterm follow-up of pediatric NAFLD patients are lacking; the studies on ancillary pharmacological interventions have been performed in few patients with inconclusive and conflicting results.

Research on the Mechanism of the treatment of non‑alcoholic fatty liver by Jianwei Gexia Zhuyu Decoction based on network pharmacology and molecular docking

Objective:To analyse the key compounds,targets and pathways of the treatment of non‑alcoholic fatty liver disease(NAFLD)by Jianwei Gexia Zhuyu Decoction based on network pharmacology,in order to explore the molecular mechanism of its therapeutic effects.Methods:The differential genes between sick and normal conditions were screened by GEO‑Datasets,and the heat map and volcano map were drawn.The active compounds in Jianwei Gexia Zhuyu Decoction were searched by TCMSP platform and Drugbank database.OB≥30%and DL≥0.18 were set as thresholds to screen potential active compounds and action targets.The molecular target maps of Jianwei Gexia Zhuyu Decoction and NAFLD differential genes were constructed,and the PPI network and network topology parameters were obtained by STRING database.The PPI network and network topology parameters were visually analyzed by Cytoscape,and the core regulatory genes were screened.At the same time,the SwissDock platform was used to dock the main active components with the target.The main pathways were determined by GO biological function enrichment analysis and KEGG metabolic pathway enrichment analysis by DAVID.Results:After screening,377 differential genes(127 up‑regulated genes and 250 down‑regulated genes),225 active compounds of Jianwei Gexia Zhuyu Decoction,308 corresponding targets were obtained;14 key targets were screened,corresponding to 168 compounds,and the key targets involved MYC,FOSL2,FOS,etc.The results of GO functional enrichment analysis showed that Jianwei Gexia Zhuyu Decoction mainly regulated the activity expression of DNA binding transcriptional activator and the specific transcription of RNA polymeraseⅡ;The results of molecular docking showed that the main active components quercetin and baicalein had good binding activity with VCAM1,HSPB1,MYC,JUN and so on;The results of KEGG enrichment analysis showed that it was mainly involved in IL‑17 signal pathway,Wnt receptor signal pathway,NF‑κB signal pathway,TNF signal pathway and AGE‑RAGE signal pathway in diabetic complications.Conclusion:Through the interaction of multi‑components and multi‑targets,Jianwei Gexia Zhuyu Decoction has achieved the goal of overall treatment of NAFLD from many ways.The application of network pharmacology provides a new research approach and scientific basis for further study on the mechanism of Jianwei Gexia Zhuyu Decoction in the treatment of NAFLD.

Dietary supplementation in patients with alcoholic liver disease: a review on current evidence

BACKGROUND：Alcoholic liver disease（ALD）is one of the main causes of liver disease worldwide.Although the pathogenesis of ALD has not yet been well elucidated,the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species play a pivotal role in the clinical and pathological spectrum of the disease.This review summarizes the existing evidences on dietary supplements considered to have antioxidant,and/or anti-inflammatory properties,and their role in the management of ALD and the proposed mechanisms.DATA SOURCES：The present study reviewed all studies published in Pub Med,Science Direct and Scopus,from 1959 to2015,indicating the role of different dietary supplementation in attenuation of many pathophysiological processes involved in development and progression of ALD.Full-texts of citations were used except for those that were published in languages other than English.RESULTS：Significant progress has been made to understand the key events and molecular players for the onset and progression of ALD from both experimental and clinical studies;however,there is no successful treatment currently available.The present review discussed the role of a variety of dietary supplements（e.g.vitamin A,carotenoids,vitamins B3,C and E,in addition to antioxidants and anti-inflammatory agents）in treating ALD.It has been shown that supplementation with some carotenoids,vitamin B3,vitamin C,silymarin,curcumin,probiotics,zinc,S-adenosylmethionine and garlic may havepotential beneficial effects in animal models of ALD;however,the number of clinical studies is very limited.In addition,supplementation should be accompanied with alcohol cessation.CONCLUSIONS：Since oxidative stress and inflammation are involved in the pathogenesis of ALD,dietary supplements that can modulate these pathologies could be useful in the treatment of ALD.In addition to alcohol cessation,these supplements have shown beneficial effects on animal models of ALD.Clinical trials are needed to validate the beneficiary role of these supplements in patients with ALD.

Gender specific medicine in liver diseases:a point of view

Gender medicine focuses on the patho-physiological, clinical, prevention and treatment differences in diseases that are equally represented in men and women. The purpose of gender medicine is to ensure that each individual man and woman receives the best treatment possible based on scientific evidence. The concept of “gender” includes not only the sexual characteristics of individuals but also physiological and psychological attributes of men and women, including risk factors, protective/aggravating effects of sexual hormones and variances linked to genetics and corporal structures that explain biological and physiological differences between men and women. It is very important to consider all the biological, physiological, functional, psychological, social and cultural characteristics to provide patients with individualized disease management. Herein, we critically analyze the literature regarding gender differences for diseases and acquired conditions of the most representative hepatic pathologies: primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, non alcoholic fatty liver disease and alcoholic liver disease, and viral chronic hepatitis B and C. The last section addresses hemochromatosis, which is a prevalent iron overload disorder in the Caucasian population. This review aims to describe data from the literature concerning viral chronic hepatitis during pregnancy, management during pregnancy and delivery, and new effective drugs for the prevention of maternal infection transmission without significant adverse effects or complications.

Deletion of Gab2 in mice protects against hepatic steatosis and steatohepatitis:a novel therapeutic target for fatty liver disease

Fatty liver disease is a serious health problem worldwide and is the most common cause for chronic liver disease and metabolic disorders.The major challenge in the prevention and intervention of this disease is the incomplete understanding of the underlying mechanism and thus lack of potent therapeutic targets due to multifaceted and interdependent disease factors.In this study,we investigated the role of a signaling adaptor protein,GRB2-associated-binding protein 2(Gab2),in fatty liver using an animal disease model.Gab2 expression in hepatocytes responded to various disease factor stimulations,and Gab2 knockout mice exhibited resistance to fat-induced obesity,fat-or alcohol-stimulated hepatic steatosis,as well as methionine and choline deficiency-induced steatohepatitis.Concordantly,the forced expression or knockdown of Gab2 enhanced or diminished oleic acid(OA)-or ethanol-induced lipid production in hepatocytes in vitro,respectively.During lipid accumulation in hepatocytes,both fat and alcohol induced the recruitment of PI3K or Socs3 by Gab2 and the activation of their downstream signaling proteins AKT,ERK,and Stat3.Therefore,Gab2 may be a disease-associated protein that is induced by pathogenic factors to amplify and coordinate multifactor-induced signals to govern disease development in the liver.Our research provides a novel potential target for the prevention and intervention of fatty liver disease.

Effects of intestine-specific deletion of fibroblast growth factor 15 on alcoholic liver disease development in mice

Background and aims:Alcoholic liver disease(ALD)is an important and growing cause for the development of chronic liver diseases in the world.Bile acid(BA)levels are increased in patients with ALD anddysregulation of BA homeostasis worsens ALD.BA synthesis is critically regulated by fibroblast growthfactor(FGF)15 in mice and FGF19 in humans.FGF15/19 are mainly produced in the ileum and their mainfunction is to suppress BA synthesis in the liver through the activation of fibroblast growth factor receptor 4(FGFR4)on hepatocytes.The effects of intestine-specific Fgf15 deficiency on the development ofALD were determined in the current study.Methods:Enterocyte-specific Fgf15 knockout mice(Fgf15intint^(-/-))and the established mouse model bychronic and binge ethanol feeding(NIAAA model)were adapted in this study.Results:The Fgf15intint^(-/-)mice had increased BA pool size,consistent with negative effects of FGF15-FGFR4signaling on BA synthesis.There were not obviously physical and hepatic histological abnormalitiespresented in Fgf15intint^(-/-)mice compared to wild-type mice.Following alcohol treatment,the Fgf15intint^(-/-)mice exhibited a higher degree of liver injury,increased hepatic expression of Cd14,a receptor forlipopolysaccharide expressed in the liver,and increased hepatic lipid levels.We did not observe alterations in the levels of fibrosis in the liver or expression of genes involved in hepatic fibrosis,regardless ofgenotypes or following the alcohol treatment.Conclusions:FGF15 may prevent hepatic steatosis in the development of ALD in mice,and maintainingFGF19/FGFR4 signaling may be critical in the prevention and/or treatment of ALD in humans in thefuture.

Regulatory T cells and their associated factors in hepatocellular carcinoma development and therapy

Liver cancer is the third leading cause of cancer-related death worldwide with primary type hepatocellular carcinoma(HCC).Factors,including carcinogens,infection of hepatitis viruses,alcohol abuse,and non-alcoholic fatty liver disease(NAFLD),can induce HCC initiation and promote HCC progression.The prevalence of NAFLD accompanying the increased incidence of obesity and type 2 diabetes becomes the most increasing factor causing HCC worldwide.However,the benefit of current therapeutic options is still limited.Intrahepatic immunity plays critically important roles in HCC initiation,development,and progression.Regulatory T cells(Tregs)and their associated factors such as metabolites and secreting cytokines mediate the immune tolerance of the tumor microenvironment in HCC.Therefore,targeting Tregs and blocking their mediated factors may prevent HCC progression.This review summarizes the functions of Tregs in HCC-inducing factors including alcoholic and NAFLD,liver fibrosis,cirrhosis,and viral infections.Overall,a better understanding of the role of Tregs in the development and progression of HCC provides treatment strategies for liver cancer treatment.

Histologically proven hepatic steatosis associates with lower testosterone levels in men with obesity

Men with obesity often present with low testosterone(T)and sex hormone-binding globulin(SHBG)levels.Several mechanisms for this have been proposed,but as SHBG is secreted by hepatocytes and sex steroids undergo hepatic metabolization,this study investigates whether severity and histological components of nonalcoholic fatty liver disease(NAFLD)are associated with sex steroid levels in obese men.This cross-sectional study included 80 obese men(age:46±11 years;body mass index:42.2±5.5 kg m^-2).Serum levels of total T and estradiol(E.)were measured using liquid chromatography coupled with tandem mass spectroscopy(LC/MS-MS)and SHBG and gonadotropins by immunoassay.Liver biopsies were evaluated using Steatosis.Activity,and Fibrosis scoring.Participants with steatohepatitis had similar median(1st quartile-3rd quartile)total T levels(7.6[5.0-11.0]nmol l^-1 vs 8.2[7.2-10.9]nmol l^-1;P=0.147),lower calculated free T(cFT)levels(148.9[122.9-188.8]pmol 1-1 s 199.5[157.3-237.6] pmol l^-1;P=0.006),and higher free E.T ratios(10.0[6.4-13.9]×10^-3 vs 7.1[5.7-10.7]×10^-3;P=0.026)compared to men with only nonalcoholic fatty liver.Among the histological components of NAFLD.only steatosis was independently associated with total T(r=-0.331.P=0.003)and cFT levels(r=-0.255.P=0.025).Obese men with.steatohepatitis have even lower cFT levels compared to those without,an association mainly driven by grade of steatosis.Whether this reflects a subgroup of men with a more severe obesity-related phenotype or results from direct relations between hepatic steatosis and sex steroid metabolism needs further investigation.