Liver diseases constitute a major healthcare burden globally,including acute hepatic injury resulted from acetaminophen overdose,ischemia-reperfusion or hepatotropic viral infection and chronic hepatitis,alcoholic liv...Liver diseases constitute a major healthcare burden globally,including acute hepatic injury resulted from acetaminophen overdose,ischemia-reperfusion or hepatotropic viral infection and chronic hepatitis,alcoholic liver disease(ALD),non-alcoholic fatty liver disease(NAFLD)and hepatocellular carcinoma(HCC).Attainable treatment strategies for most liver diseases remain inadequate,highlighting the importance of substantial pathogenesis.The transient receptor potential(TRP)channels represent a versatile signalling mechanism regulating fundamental physiological processes in the liver.It is not surprising that liver diseases become a newly explored field to enrich our knowledge of TRP channels.Here,we discuss recent findings revealing TRP functions across the fundamental pathological course from early hepatocellular injury caused by various insults,to inflammation,subsequent fibrosis and hepatoma.We also explore expression levels of TRPs in liver tissues of ALD,NAFLD and HCC patients from Gene Expression Omnibus(GEO)or The Cancer Genome Atlas(TCGA)database and survival analysis estimated by Kaplan-Meier Plotter.At last,we address the therapeutical potential and challenges by pharmacologically targeting TRPs to treat liver diseases.The aim is to provide a better understanding of the implications of TRP channels in liver diseases,contributing to the discovery of novel therapeutic targets and efficient drugs.展开更多
Alcohol-related liver disease(ALD)became an important health issue worldwide.Following chronic alcohol consumption,the development of ALD might be caused by metabolic and immunologic factors,such as reactive oxygen sp...Alcohol-related liver disease(ALD)became an important health issue worldwide.Following chronic alcohol consumption,the development of ALD might be caused by metabolic and immunologic factors,such as reactive oxygen species(ROS)and pro-inflammatory cytokines.For example,hepatic cytochrome P4502E1 enzyme increases ROS production and stimulates de novo lipogenesis after alcohol exposure.In addition,damage-and pathogen-associated molecular patterns stimulate their specific receptors in nonparenchymal cells,including Kupffer cells,hepatic stellate cells(HSCs),and lymphocytes,which result in hepatocyte death and infiltration of pro-inflammatory cells(e.g.,neutrophils and macrophages)in the liver.Moreover,our studies have suggested the novel involvement of neurologic signaling pathways(e.g.,endocannabinoid and glutamate)through the metabolic synapse between hepatocytes and HSCs in the development of alcohol-related hepatic steatosis.Additionally,agouti-related protein and beta2-adrenergic receptors aggravate hepatic steatosis.Furthermore,organ-crosstalk has emerged as a critical issue in ALD.Chronic alcohol consumption induces dysbiosis and barrier disruption in the gut,leading to endotoxin leakage into the portal circulation,or lipolysis-mediated transport of triglycerides from the adipose tissue to the liver.In summary,this review addresses multiple pathogeneses of ALD,provides novel neurologic signaling pathways,and emphasizes the importance of organ-crosstalk in the development of ALD.展开更多
Alcoholic liver disease(ALD)has a multifaceted development,progressing from alcoholic steatosis to alcoholic hepatitis and ultimately to alcoholic cirrhosis,irreversible liver damage that can even result in hepatocell...Alcoholic liver disease(ALD)has a multifaceted development,progressing from alcoholic steatosis to alcoholic hepatitis and ultimately to alcoholic cirrhosis,irreversible liver damage that can even result in hepatocellular carcinoma.The prevalence of ALD is increasing globally,particularly among middle-aged adults.Gender-based studies have revealed that ALD affects more men;however,disease progression differs between men and women.Despite this,the molecular understanding of alcohol-induced liver injury among genders and its association with changes in sex hormone metabolism,particularly with estrogen and estrogen receptors(ERs)in ALD,remains poor.This review focuses on experimental and human studies describing alcohol and its association with estrogen metabolism and signaling via ERs.Chronic alcohol consumption affects the immune response,and whether estrogen has any contributory effect remains inadequately studied.This review also discusses various therapeutic approaches currently in use and future approaches that can affect the response or progression via estrogen signaling.The role of gender on alcohol consumption and its association with steroid hormones must be elucidated for a better understanding of the pathogenesis of ALD,the development of effective therapeutic approaches,and better disease management in both men and women,as ALD remains a major public health concern.展开更多
Alcoholic liver disease(ALD)encompasses a range of conditions resulting from prolonged and excessive alcohol consumption,causing liver damage such as alcoholic fatty liver,inflammation,fibrosis,and cirrhosis.Alcohol c...Alcoholic liver disease(ALD)encompasses a range of conditions resulting from prolonged and excessive alcohol consumption,causing liver damage such as alcoholic fatty liver,inflammation,fibrosis,and cirrhosis.Alcohol consumption contributes to millions of deaths each year.So far,the effective treatments for ALD are limited.To date,the most effective treatment for ALD is still prevention by avoiding excessive alcohol consumption,and only few specialized medicines are in the market for the treatment of patients suffering from ALD.Small molecules targeting various pathways implicated in ALD pathogenesis can potentially be used for effective therapeutics development.In this review,we provide a concise overview of the latest research findings on potential therapeutic targets,specifically emphasizing small-molecule interventions for the treatment and prevention of ALD.展开更多
Louvet et al.recently published the French Association for the Study of the Liver(AFEF)and the French Alcohol Society clinical guidelines(1).The AFEF guidelines are the first specific to the screening and care of alco...Louvet et al.recently published the French Association for the Study of the Liver(AFEF)and the French Alcohol Society clinical guidelines(1).The AFEF guidelines are the first specific to the screening and care of alcohol-related liver disease(ALD)in France.We compared these to the guidelines of American Association for the Study of Liver Diseases[AASLD,2020;(2)]and European Association for the Study of Liver[EASL,2018(3)];some noticeable differences and similarities emerge(Table 1).展开更多
目的利用生物信息学方法探索酒精性肝病(alcoholic liver disease,ALD)潜在的关键基因并通过实验验证,为寻找ALD潜在的生物标志物提供依据。方法从美国国立生物技术信息中心(National Center for Biotechnology Information,NCBI)的公...目的利用生物信息学方法探索酒精性肝病(alcoholic liver disease,ALD)潜在的关键基因并通过实验验证,为寻找ALD潜在的生物标志物提供依据。方法从美国国立生物技术信息中心(National Center for Biotechnology Information,NCBI)的公共基因芯片数据平台(Gene Expression Omnibus,GEO)的数据库下载两个基因表达谱芯片(GSE28619和GSE100901),利用GEO2R筛选出酒精性肝病实验组与正常对照组的差异表达基因(differentially expressed genes,DEGs),对DEGs进行基因本体论(gene ontology,GO)与京都基因和基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)信号通路的富集分析,进一步应用STRING数据库构建蛋白质的相互作用网络,用Cytoscape来筛选出关键基因。构建ALD小鼠模型,通过RT-qPCR验证筛选出关键基因。结果总共鉴定出173个DEGs,GO显示DEGs生物学功能主要涉及5个KEGG通路,包括补体和凝血级联、胆固醇代谢、视黄醇代谢、药物代谢-细胞色素P450、胆汁分泌相关信号通路,结合蛋白质相互作用网络(protein-protein interaction,PPI)和CytoHubba的结果,筛选出SERPINC1、AHSG、FGG、FGA、ITIH3、FGB、APOB、ALB和APOH 9个关键基因,通过RT-qPCR检测验证,发现与WT小鼠相比,ALD小鼠肝脏ALB、APOB和FGB的mRNA表达上调(P<0.05),而ITIH3、FGG和SERPINC1的mRNA表达下调(P<0.05)。结论ALB、APOB、FGB、ITIH3、FGG、SERPINC1有望成为ALD潜在的生物标志物。展开更多
Autophagy is an evolutionarily conserved intracellular degradative function that is important for liver homeostasis.Accumulating evidence suggests that autophagy is deregulated during the progression and development o...Autophagy is an evolutionarily conserved intracellular degradative function that is important for liver homeostasis.Accumulating evidence suggests that autophagy is deregulated during the progression and development of alcoholic and non-alcoholic liver diseases.Impaired autophagy prevents the clearance of excessive lipid droplets(LDs),damaged mitochondria,and toxic protein aggregates,which can be generated during the progression of various liver diseases,thus contributing to the development of steatosis,injury,steatohepatitis,fibrosis,and tumors.In this review,we look at the status of hepatic autophagy during the pathogenesis of alcoholic and non-alcoholic liver diseases.We also examine the mechanisms of defects in autophagy,and the hepato-protective roles of autophagy in non-alcoholic fatty liver disease(NAFLD)and alcoholic liver disease(ALD),focusing mainly on steatosis and liver injury.Finally,we discuss the therapeutic potential of autophagy modulating agents for the treatment of these two common liver diseases.展开更多
The 4th Chinese American Liver Society(CALS)/Society of Chinese Bioscientists in America(SCBA)Hepatology Division Annual Symposium was held virtually on October 29e30,2021.The goal of the CALS Symposium was to present...The 4th Chinese American Liver Society(CALS)/Society of Chinese Bioscientists in America(SCBA)Hepatology Division Annual Symposium was held virtually on October 29e30,2021.The goal of the CALS Symposium was to present and discuss the recent research data on the pathogenesis and therapeutic targets of liver diseases among the CALS members,trainees and invited speakers.Here we briefly introduce the history of the CALS/SCBA Hepatology Division and highlight the presentations that focus on the current progresses on basic and translational research in liver metabolism,bile acid biology,alcohol-related liver disease,drug-induced liver injury,cholestatic liver injury,non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and liver cancer.展开更多
Heavy alcohol use is the cause of alcoholic liver disease(ALD).The ALD spectrum ranges from alcoholic steatosis to steatohepatitis,fibrosis,and cirrhosis.In Western countries,approximately 50%of cirrhosis-related deat...Heavy alcohol use is the cause of alcoholic liver disease(ALD).The ALD spectrum ranges from alcoholic steatosis to steatohepatitis,fibrosis,and cirrhosis.In Western countries,approximately 50%of cirrhosis-related deaths are due to alcohol use.While alcoholic cirrhosis is no longer considered a completely irreversible condition,no effective anti-fibrotic therapies are currently available.Another significant clinical aspect of ALD is alcoholic hepatitis(AH).AH is an acute inflammatory condition that is often comorbid with cirrhosis,and severe AH has a high mortality rate.Therapeutic options for ALD are limited.The established treatment for AH is corticosteroids,which improve short-term survival but do not affect long-term survival.Liver transplantation is a curative treatment option for alcoholic cirrhosis and AH,but patients must abstain from alcohol use for 6 months to qualify.Additional effective therapies are needed.The molecular mechanisms underlying ALD are complex and have not been fully elucidated.Various molecules,signaling pathways,and crosstalk between multiple hepatic and extrahepatic cells contribute to ALD progression.This review highlights established and emerging concepts in ALD clin-icopathology,their underlying molecular mechanisms,and current and future ALD treatment options.展开更多
Alcohol consumption remains one of the predominant causes of liver disease and liver-related death worldwide.Intriguingly,dysregulation of the gut barrier is a key factor promoting the pathogenesis of alcoholic liver ...Alcohol consumption remains one of the predominant causes of liver disease and liver-related death worldwide.Intriguingly,dysregulation of the gut barrier is a key factor promoting the pathogenesis of alcoholic liver disease(ALD).A functional gut barrier,which consists of a mucus layer,an intact epithelial monolayer and mucosal immune cells,supports nutrient absorption and prevents bacterial penetration.Compromised gut barrier function is associated with the progression of ALD.Indeed,alcohol consumption disrupts the gut barrier,increases gut permeability,and induces bacterial translocation both in ALD patients and in experimental models with ALD.Moreover,alcohol consumption also causes enteric dysbiosis with both numerical and proportional perturbations.Here,we review and discuss mechanisms of alcohol-induced gut barrier dysfunction to better understand the contribution of the gut-liver axis to the pathogenesis of ALD.Unfortunately,there is no effectual Food and Drug Administration-approved treatment for any stage of ALD.Therefore,we conclude with a discussion of potential strategies aimed at restoring the gut barrier in ALD.The principle behind antibiotics,prebiotics,probiotics and fecal microbiota transplants is to restore microbial symbiosis and subsequently gut barrier function.Nutrientbased treatments,such as dietary supplementation with zinc,niacin or fatty acids,have been shown to regulate tight junction expression,reduce intestinal inflammation,and prevent endotoxemia as well as liver injury caused by alcohol in experimental settings.Interestingly,saturated fatty acids may also directly control the gut microbiome.In summary,clinical and experimental studies highlight the significance and efficacy of the gut barrier in treating ALD.展开更多
Fatty liver diseases including alcoholic liver disease(ALD)and non-alcoholic fatty liver disease(NAFLD)are leading causes of chronic liver diseases worldwide.ALD and NAFLD encompass a broad spectrum of liver disorders...Fatty liver diseases including alcoholic liver disease(ALD)and non-alcoholic fatty liver disease(NAFLD)are leading causes of chronic liver diseases worldwide.ALD and NAFLD encompass a broad spectrum of liver disorders ranging from simple steatosis to steatohepatitis,fibrosis,cirrhosis and superimposed hepatocellular carcinoma.Despite considerable advances in our understanding of the pathogenesis of fatty liver diseases over the past 40 years,effective diagnostic,prognostic,and therapeutic tools are still lacking.The use of animal models is crucial to investigate the cellular and molecular mechanisms underlying the development and progression of fatty liver diseases and develop novel therapeutic strategies.Although no animal model to date can faithfully replicate all the clinical and histological features of ALD or NAFLD,existing models can mimic specific aspects of human diseases.This review provides an overview of the most commonly used and recently developed rodent models of ALD and NAFLD and discusses their major strengths and shortcomings.展开更多
Alcohol-related liver disease(ALD),which is caused by excessive alcohol consumption,is one of the most common types of liver disease and a primary cause of hepatic injury,with a disease spectrum that in-cludes steatos...Alcohol-related liver disease(ALD),which is caused by excessive alcohol consumption,is one of the most common types of liver disease and a primary cause of hepatic injury,with a disease spectrum that in-cludes steatosis,steatohepatitis,fibrosis,cirrhosis,and hepatocellular carcinoma.Various lines of evi-dence have indicated that immune cells play a significant role in the inflammatory processes of ALD.On the one hand,the liver contains various resident immune cells that have been proven to perform different functions in ALD.For example,in the progression of the disease,Kupffer cells(KCs)are activated by lipopolysaccharide-Toll-like receptor 4 signaling and release various proinflammatory cytokines.Moreover,alcohol intake has been shown to depress the function of natural killer cells.Additionally,two types of unconventional T cells(natural killer T cells and mucosal-associated invariant T cells)are involved in the development of ALD.On the other hand,alcohol and many different cytokines stimulate the recruitment and infiltration of circulating immune cells(neutrophils,T cells,macrophages,and mast cells)into the liver.The neutrophils can produce proinflammatory mediators and cause the dysfunction of anti-infection processes.Additionally,alcohol intake can change the phenotype of T cells,resulting in their increased production of interleukin-17.Aside from KCs,infiltrating macrophages have also been observed in patients with ALD,but the roles of all of these cells in the progression of the disease have shown both similarities and differences.Additionally,the activated mast cells are also associated with the development of ALD.Herein,we review the diverse roles of the various immune cells in the progression of ALD.展开更多
The review describes research findings on the influence of alcohol consumption on two crucial catabolic systems in hepatocytes:the lysosome and the ubiquitin-proteasome system(UPS).The lysosome is a membrane-bound org...The review describes research findings on the influence of alcohol consumption on two crucial catabolic systems in hepatocytes:the lysosome and the ubiquitin-proteasome system(UPS).The lysosome is a membrane-bound organelle that degrades all aging and/or damaged organelles and hydrolyzes all forms of macromolecules.The UPS is mostly proteolytic.It carries out the majority of its functions in the soluble portion of the cytoplasm(cytosol)and degrades nearly all intracellular proteins,particularly those with short half-lives,so that their levels are tightly controlled.Our review will briefly discuss the epidemiology of alcohol abuse and the spectrum of alcohol-induced liver disease(AILD).We will explain why ethanol(EtOH)metabolism,but not EtOH alone,is hepatotoxic.Then,we will summarize how heavy drinking alters hepatic catabolic systems,resulting in liver enlargement that develops from hepatocyte swelling due,in part,to aberrant accumulation of undegraded lipid droplets(steatosis)and undegraded proteins(proteopathy).Our detailed description of each catabolic system will highlight its discoverer(s)and emphasize each system’s characteristics.Most important,we will review the evidence that chronic EtOH consumption disrupts hepatic lysosome biogenesis and inhibits the UPS by impeding hepatic proteasome activity.It will become evident that each of these EtOH-induced defects has far-reaching functional consequences.Finally,we will describe current and potential therapeutic interventions for alleviating EtOH-induced liver injury.The most effective intervention is the cessation of EtOH consumption.However,there are other potential approaches using natural or synthetic compounds that activate autophagy or the proteasome to enhance the degradation of accumulated lipid droplets or proteins,respectively,which could alleviate AILD.These approaches,now in their early stages of investigation,will also be discussed in this review.展开更多
Alcoholic liver disease(ALD)remains one of the leading causes of liver injury and death when left un-treated.The gut microbiota has been recognized as a key regulator of a number of pathologies,including ALD.The role ...Alcoholic liver disease(ALD)remains one of the leading causes of liver injury and death when left un-treated.The gut microbiota has been recognized as a key regulator of a number of pathologies,including ALD.The role of mast cells(MCs)during liver disease progression has been demonstrated in a number of animal models and in human liver diseases.The interaction between the gut microbiota and MCs has been investigated,and links between the gut and these immune cells are being uncovered.The interplay between the gut microbiota and MCs during ALD has been evaluated and studies suggest that there could be an important link between MCs,their mediators and gut inflammation during the progression of ALD.展开更多
Cytokines are considered crucial players in inflammatory-associated disorders throughout the body.Fatty liver diseases such as alcoholic liver disease(ALD)and non-alcoholic fatty liver disease(NAFLD)are commonly chara...Cytokines are considered crucial players in inflammatory-associated disorders throughout the body.Fatty liver diseases such as alcoholic liver disease(ALD)and non-alcoholic fatty liver disease(NAFLD)are commonly characterized by lipid accumulation and in a substantial subset of patients with inflammation in the liver.Amount of inflammation affects long-term outcome of liver disease including evolution of liver fibrosis,cirrhosis and hepatocellular carcinoma.Especially the pro-inflammatory cytokines Interleukin(IL)-1(αandβ)and tumor necrosis factor(TNF)αplay a central role in many stages of liver diseases mediating fundamental aspects of those diseases including acute phase protein synthesis,lipid metabolism,cholestasis and degree of fibrosis.These key cytokines released mainly by mononuclear cells affect all liver cell types and orchestrate the production of many other mediators relevant in chronic liver diseases.Inflammatory cytokines also regulate crucially the development of insulin resistance,a key component of NAFLD.Blocking these critical mediators of inflammation by specific antibodies,especially TNFα,has so far not been proven successful in alcoholic steatohepatitis,a cytokine-driven disorder.In summary,inflammatory cytokines are continuously present locally and systemically in patients with advanced fatty liver diseases,mediating and affecting the clinical phenotype and many features of these disorders.展开更多
Alcoholic liver disease(ALD)represents a wide spectrum of disease from simple steatosis to cirrhosis.Although there have been multiple attempts to treat ALD,its treatment is still based on abstinence from alcohol and ...Alcoholic liver disease(ALD)represents a wide spectrum of disease from simple steatosis to cirrhosis.Although there have been multiple attempts to treat ALD,its treatment is still based on abstinence from alcohol and using corticosteroids in specified cases.However,nearly 40%of patients with ALD who are in need of treatment are unresponsive to the current treatments,which implies a new paradigm shift for the treatment of ALD.Traditionally,earlier studies have focused on the abnormal metabolism occurring in the hepatocytes as a protagonist in the pathogenesis of ALD.However,increasing evidence suggests that non-parenchymal cells,such as hepatic stellate cells(HSCs),Kupffer cells,liver sinusoidal endothelial cells,and immune cells around the hepatocytes have critical roles in multiple stages of ALD either by direct or indirect cell-to-cell interactions.For instance,in the early stage of ALD,Kupffer cells and HSCs located closely to hepatocytes contribute to the development of alcoholic steatosis and inflammation through the secretion of various inflammatory cytokines(immunologic pathways)and the activation of the endocannabinoid system(metabolic pathways).While the stage of ALD progresses to alcoholic hepatitis and fibrosis,various cell-to-cell interactions with infiltrating immune cells become highly significant at the multicellular level.This review explains the diverse roles of non-parenchymal cells in the progression of ALD,as well as potential therapeutic strategies to treat ALD.展开更多
Inflammation,which is mediated by leukocyte trafficking and activation,plays a prominent role in the pathogenesis of acute and chronic liver injury.Chemokines are critical mediators involved in the migration of leukoc...Inflammation,which is mediated by leukocyte trafficking and activation,plays a prominent role in the pathogenesis of acute and chronic liver injury.Chemokines are critical mediators involved in the migration of leukocytes into the diseased liver via binding to their G protein-coupled receptors.CeC motif ligand 5(CCL5)belongs to the CC-chemokine family and is secreted by several hepatic cell pop-ulations including hepatocytes,macrophages,hepatic stellate cells,and endothelial cells upon activation.CCL5 regulates the recruitment and migration of T cells(via CCR5)and NK cells(via CCR1).Moreover,CCL5 activates and stimulates T cell proliferation and cytokine production,sequentially regulating in-flammatory responses.Accumulating studies have identified crucial effects of CCL5 both in liver-disease patients and in experimental models,in which CCL5 is elevated and displays distinct effects according to pathological conditions.In this review,we discussed the crucial functions of CCL5 in liver diseases,including acute liver failure,hepatic ischemia-reperfusion injury,acute liver failure,acute and viral hepatitis,alcoholic liver disease,non-alcoholic fatty liver disease,fibrosis,and hepatocellular carcinoma.Continued understanding the roles of CCL5 in liver disease and their mechanisms of activation are indispensable for the development of effective clinical therapeutics.展开更多
Alcoholic liver disease(ALD)comprises a spectrum of liver pathology,including steatosis,steatohepatitis,and cirrhosis.Previous work from our group and others suggests that dietary fat,both the amount and composition,p...Alcoholic liver disease(ALD)comprises a spectrum of liver pathology,including steatosis,steatohepatitis,and cirrhosis.Previous work from our group and others suggests that dietary fat,both the amount and composition,plays a pivotal role in ALD development and progression;however,the impact of specific dietary fatty acids on ALD pathogenesis is not fully elucidated.Preclinical rodent models of ALD revealed the deleterious effects of omega-6 polyunsaturated fatty acids(n-6 PUFAs),specifically linoleic acid(LA),and this may be partially attributed to the increased levels of pro-inflammatory oxidized LA metabolites.There is limited understanding regarding the role of omega-3 polyunsaturated fatty acids(n-3 PUFAs,such as alpha-linolenic acid,eicosapentaenoic acid,and docosahexaenoic acid),and bioactive n-3 PUFAderived lipid molecules in ALD.Given that majority of n-6 and n-3 PUFAs-derived metabolites are potent endogenous signaling molecules,knowledge regarding the changes in these lipid mediators may shed new light on the mechanisms contributing to ALD pathogenesis and reveal novel therapeutic targets and biomarkers of this disease.The current review summarizes relevant scientific literature regarding the role of dietary fat,distinct fatty acids,and bioactive fatty acid metabolites in ALD,and highlights recent advances in the field.展开更多
Background:Alcohol-associated liver disease(ALD)is a major chronic liver disease around the world without successful treatment.Acute alcoholic hepatitis is one of the most severe forms of ALD with high mortality,which...Background:Alcohol-associated liver disease(ALD)is a major chronic liver disease around the world without successful treatment.Acute alcoholic hepatitis is one of the most severe forms of ALD with high mortality,which is often associated with binge drinking.Alcohol drinking dysregulates lipid metabolism,increases adipose tissue lipolysis,and induces liver steatosis and adipose tissue atrophy.Increasing ev-idence implicates that crosstalk of liver and adipose tissue in the pathogenesis of ALD.Mechanistic target of rapamycin(mTOR)is a phosphatidylinositol 3-kinase(PI3K)-like serine/threonine protein kinase that regulates lipid metabolism,cell proliferation and autophagy.However,the role of mTOR in regulating adipose-liver crosstalk in binge drinking-induced organ damage remains unclear.Methods:We generated liver-specific and adipocyte-specific regulatory-associated protein of mTOR(Rptor)knockout(Rptor LKO and Rptor AKO)as well as Mtor knockout(Mtor LKO and Mtor AKO)mice,by crossing Rptor flox and Mtor flox mice with albumin Cre or adiponectin Cre mice,respectively.In addition,we generated liver and adipocyte double deletion of Rptor or Mtor(Mtor LAKO and Rptor LAKO)mice.The knockout mice with their matched wild-type littermates(Rptor WT and Mtor WT)were subjected to acute gavage of 7 g/kg ethanol.Results:Mice with adipocyte deletion of Rptor or Mtor developed hepatomegaly and adipose tissue at-rophy.Alcohol gavage increased liver injury,hepatic steatosis and inflammation in mouse livers as demonstrated by elevated serum alanine aminotransferase activities,increased hepatic levels of tri-glyceride and increased hepatic numbers of CD68 positive macrophages in mouse livers after alcohol gavage.Liver injury was further exacerbated by deletion of adipocyte Rptor or Mtor.Serum adipokine array analysis revealed that increased levels of pro-inflammatory cytokines IL-6 and TNF a as well as chemokine MCP-1 following acute alcohol gavage in wild-type mice,which were further increased in adipocyte-specific Mtor or Rptor knockout mice.Conversely,levels of anti-inflammatory cytokine IL-10 decreased in adipocyte-specific Mtor or Rptor knockout mice.The levels of circulating fibroblast growth factor 21(FGF21)increased whereas levels of circulating adiponectin and fetuin A decreased in wild-type mice after alcohol gavage.Intriguingly,adipocyte-specific Mtor or Rptor knockout mice already had decreased basal level of FGF21 which increased by alcohol gavage.Moreover,adipocyte-specific Mtor or Rptor knockout mice already had increased basal level of adiponectin and decreased fetuin A which were not further changed by alcohol gavage.Conclusions:Adipocyte but not hepatocyte ablation of Mtor pathway contributes to acute alcohol-induced liver injury with increased inflammation.Our results demonstrate the critical role of adipo-cyte mTOR in regulating the adipose-liver crosstalk in ALD.展开更多
基金supported by National Natural Science Foundation of China(81902480)the Fundamental Research Funds for the Central Universities(2632019PY04,China)+9 种基金the Jiangsu Provincial Double-Innovation Doctor ProgramNanjing Science and Technology Innovation Project to Wenhui WangNatural Science Foundation of Jiangsu Province(BK20202002,China)National Natural Science Foundation of China(31971146)Innovation and Entrepreneurship Talent Program of Jiangsu ProvinceGuangxi Funds for Distinguished Experts“Xing Yao”Leading Scholars of China Pharmaceutical University(2021)to Ye Yu(China)China Postdoctoral Science Foundation(2020T130279 and 2020M682812,China)Basic and Applied Basic Research Foundation of Guangdong Province of China(2021A1515011085)to Pengyu LiuNational Natural Science Foundation of China(32000869)to Jin Wang。
文摘Liver diseases constitute a major healthcare burden globally,including acute hepatic injury resulted from acetaminophen overdose,ischemia-reperfusion or hepatotropic viral infection and chronic hepatitis,alcoholic liver disease(ALD),non-alcoholic fatty liver disease(NAFLD)and hepatocellular carcinoma(HCC).Attainable treatment strategies for most liver diseases remain inadequate,highlighting the importance of substantial pathogenesis.The transient receptor potential(TRP)channels represent a versatile signalling mechanism regulating fundamental physiological processes in the liver.It is not surprising that liver diseases become a newly explored field to enrich our knowledge of TRP channels.Here,we discuss recent findings revealing TRP functions across the fundamental pathological course from early hepatocellular injury caused by various insults,to inflammation,subsequent fibrosis and hepatoma.We also explore expression levels of TRPs in liver tissues of ALD,NAFLD and HCC patients from Gene Expression Omnibus(GEO)or The Cancer Genome Atlas(TCGA)database and survival analysis estimated by Kaplan-Meier Plotter.At last,we address the therapeutical potential and challenges by pharmacologically targeting TRPs to treat liver diseases.The aim is to provide a better understanding of the implications of TRP channels in liver diseases,contributing to the discovery of novel therapeutic targets and efficient drugs.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Ministry of Science and ICT,Korean goverment(2021R1A2C3004589,2014M3A9D5A01073556).
文摘Alcohol-related liver disease(ALD)became an important health issue worldwide.Following chronic alcohol consumption,the development of ALD might be caused by metabolic and immunologic factors,such as reactive oxygen species(ROS)and pro-inflammatory cytokines.For example,hepatic cytochrome P4502E1 enzyme increases ROS production and stimulates de novo lipogenesis after alcohol exposure.In addition,damage-and pathogen-associated molecular patterns stimulate their specific receptors in nonparenchymal cells,including Kupffer cells,hepatic stellate cells(HSCs),and lymphocytes,which result in hepatocyte death and infiltration of pro-inflammatory cells(e.g.,neutrophils and macrophages)in the liver.Moreover,our studies have suggested the novel involvement of neurologic signaling pathways(e.g.,endocannabinoid and glutamate)through the metabolic synapse between hepatocytes and HSCs in the development of alcohol-related hepatic steatosis.Additionally,agouti-related protein and beta2-adrenergic receptors aggravate hepatic steatosis.Furthermore,organ-crosstalk has emerged as a critical issue in ALD.Chronic alcohol consumption induces dysbiosis and barrier disruption in the gut,leading to endotoxin leakage into the portal circulation,or lipolysis-mediated transport of triglycerides from the adipose tissue to the liver.In summary,this review addresses multiple pathogeneses of ALD,provides novel neurologic signaling pathways,and emphasizes the importance of organ-crosstalk in the development of ALD.
文摘Alcoholic liver disease(ALD)has a multifaceted development,progressing from alcoholic steatosis to alcoholic hepatitis and ultimately to alcoholic cirrhosis,irreversible liver damage that can even result in hepatocellular carcinoma.The prevalence of ALD is increasing globally,particularly among middle-aged adults.Gender-based studies have revealed that ALD affects more men;however,disease progression differs between men and women.Despite this,the molecular understanding of alcohol-induced liver injury among genders and its association with changes in sex hormone metabolism,particularly with estrogen and estrogen receptors(ERs)in ALD,remains poor.This review focuses on experimental and human studies describing alcohol and its association with estrogen metabolism and signaling via ERs.Chronic alcohol consumption affects the immune response,and whether estrogen has any contributory effect remains inadequately studied.This review also discusses various therapeutic approaches currently in use and future approaches that can affect the response or progression via estrogen signaling.The role of gender on alcohol consumption and its association with steroid hormones must be elucidated for a better understanding of the pathogenesis of ALD,the development of effective therapeutic approaches,and better disease management in both men and women,as ALD remains a major public health concern.
基金supported by the National Institute of Diabetes and Digestive and Kidney(R01-DK121970)to Dr.Feng Li.
文摘Alcoholic liver disease(ALD)encompasses a range of conditions resulting from prolonged and excessive alcohol consumption,causing liver damage such as alcoholic fatty liver,inflammation,fibrosis,and cirrhosis.Alcohol consumption contributes to millions of deaths each year.So far,the effective treatments for ALD are limited.To date,the most effective treatment for ALD is still prevention by avoiding excessive alcohol consumption,and only few specialized medicines are in the market for the treatment of patients suffering from ALD.Small molecules targeting various pathways implicated in ALD pathogenesis can potentially be used for effective therapeutics development.In this review,we provide a concise overview of the latest research findings on potential therapeutic targets,specifically emphasizing small-molecule interventions for the treatment and prevention of ALD.
基金This study was supported,in part,by grants from NIH(Nos.R01 AA021978 and P30 DK120531).
文摘Louvet et al.recently published the French Association for the Study of the Liver(AFEF)and the French Alcohol Society clinical guidelines(1).The AFEF guidelines are the first specific to the screening and care of alcohol-related liver disease(ALD)in France.We compared these to the guidelines of American Association for the Study of Liver Diseases[AASLD,2020;(2)]and European Association for the Study of Liver[EASL,2018(3)];some noticeable differences and similarities emerge(Table 1).
文摘目的利用生物信息学方法探索酒精性肝病(alcoholic liver disease,ALD)潜在的关键基因并通过实验验证,为寻找ALD潜在的生物标志物提供依据。方法从美国国立生物技术信息中心(National Center for Biotechnology Information,NCBI)的公共基因芯片数据平台(Gene Expression Omnibus,GEO)的数据库下载两个基因表达谱芯片(GSE28619和GSE100901),利用GEO2R筛选出酒精性肝病实验组与正常对照组的差异表达基因(differentially expressed genes,DEGs),对DEGs进行基因本体论(gene ontology,GO)与京都基因和基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)信号通路的富集分析,进一步应用STRING数据库构建蛋白质的相互作用网络,用Cytoscape来筛选出关键基因。构建ALD小鼠模型,通过RT-qPCR验证筛选出关键基因。结果总共鉴定出173个DEGs,GO显示DEGs生物学功能主要涉及5个KEGG通路,包括补体和凝血级联、胆固醇代谢、视黄醇代谢、药物代谢-细胞色素P450、胆汁分泌相关信号通路,结合蛋白质相互作用网络(protein-protein interaction,PPI)和CytoHubba的结果,筛选出SERPINC1、AHSG、FGG、FGA、ITIH3、FGB、APOB、ALB和APOH 9个关键基因,通过RT-qPCR检测验证,发现与WT小鼠相比,ALD小鼠肝脏ALB、APOB和FGB的mRNA表达上调(P<0.05),而ITIH3、FGG和SERPINC1的mRNA表达下调(P<0.05)。结论ALB、APOB、FGB、ITIH3、FGG、SERPINC1有望成为ALD潜在的生物标志物。
基金This work was supported in part by the USA National Institutes of Health(NIH)grants R01AA021751 and R21AA021450(to X.-M.Yin).
文摘Autophagy is an evolutionarily conserved intracellular degradative function that is important for liver homeostasis.Accumulating evidence suggests that autophagy is deregulated during the progression and development of alcoholic and non-alcoholic liver diseases.Impaired autophagy prevents the clearance of excessive lipid droplets(LDs),damaged mitochondria,and toxic protein aggregates,which can be generated during the progression of various liver diseases,thus contributing to the development of steatosis,injury,steatohepatitis,fibrosis,and tumors.In this review,we look at the status of hepatic autophagy during the pathogenesis of alcoholic and non-alcoholic liver diseases.We also examine the mechanisms of defects in autophagy,and the hepato-protective roles of autophagy in non-alcoholic fatty liver disease(NAFLD)and alcoholic liver disease(ALD),focusing mainly on steatosis and liver injury.Finally,we discuss the therapeutic potential of autophagy modulating agents for the treatment of these two common liver diseases.
文摘The 4th Chinese American Liver Society(CALS)/Society of Chinese Bioscientists in America(SCBA)Hepatology Division Annual Symposium was held virtually on October 29e30,2021.The goal of the CALS Symposium was to present and discuss the recent research data on the pathogenesis and therapeutic targets of liver diseases among the CALS members,trainees and invited speakers.Here we briefly introduce the history of the CALS/SCBA Hepatology Division and highlight the presentations that focus on the current progresses on basic and translational research in liver metabolism,bile acid biology,alcohol-related liver disease,drug-induced liver injury,cholestatic liver injury,non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and liver cancer.
基金This work was supported by the National Institutes of Health(NIH)grants R01DK085252,R01AA027036,R21AA025841 and a Winnick Research Award from Cedars-Sinai Medical Center.
文摘Heavy alcohol use is the cause of alcoholic liver disease(ALD).The ALD spectrum ranges from alcoholic steatosis to steatohepatitis,fibrosis,and cirrhosis.In Western countries,approximately 50%of cirrhosis-related deaths are due to alcohol use.While alcoholic cirrhosis is no longer considered a completely irreversible condition,no effective anti-fibrotic therapies are currently available.Another significant clinical aspect of ALD is alcoholic hepatitis(AH).AH is an acute inflammatory condition that is often comorbid with cirrhosis,and severe AH has a high mortality rate.Therapeutic options for ALD are limited.The established treatment for AH is corticosteroids,which improve short-term survival but do not affect long-term survival.Liver transplantation is a curative treatment option for alcoholic cirrhosis and AH,but patients must abstain from alcohol use for 6 months to qualify.Additional effective therapies are needed.The molecular mechanisms underlying ALD are complex and have not been fully elucidated.Various molecules,signaling pathways,and crosstalk between multiple hepatic and extrahepatic cells contribute to ALD progression.This review highlights established and emerging concepts in ALD clin-icopathology,their underlying molecular mechanisms,and current and future ALD treatment options.
基金This work was supported by the USA National Institutes of Health(R01AA020212 and R01AA018844).
文摘Alcohol consumption remains one of the predominant causes of liver disease and liver-related death worldwide.Intriguingly,dysregulation of the gut barrier is a key factor promoting the pathogenesis of alcoholic liver disease(ALD).A functional gut barrier,which consists of a mucus layer,an intact epithelial monolayer and mucosal immune cells,supports nutrient absorption and prevents bacterial penetration.Compromised gut barrier function is associated with the progression of ALD.Indeed,alcohol consumption disrupts the gut barrier,increases gut permeability,and induces bacterial translocation both in ALD patients and in experimental models with ALD.Moreover,alcohol consumption also causes enteric dysbiosis with both numerical and proportional perturbations.Here,we review and discuss mechanisms of alcohol-induced gut barrier dysfunction to better understand the contribution of the gut-liver axis to the pathogenesis of ALD.Unfortunately,there is no effectual Food and Drug Administration-approved treatment for any stage of ALD.Therefore,we conclude with a discussion of potential strategies aimed at restoring the gut barrier in ALD.The principle behind antibiotics,prebiotics,probiotics and fecal microbiota transplants is to restore microbial symbiosis and subsequently gut barrier function.Nutrientbased treatments,such as dietary supplementation with zinc,niacin or fatty acids,have been shown to regulate tight junction expression,reduce intestinal inflammation,and prevent endotoxemia as well as liver injury caused by alcohol in experimental settings.Interestingly,saturated fatty acids may also directly control the gut microbiome.In summary,clinical and experimental studies highlight the significance and efficacy of the gut barrier in treating ALD.
文摘Fatty liver diseases including alcoholic liver disease(ALD)and non-alcoholic fatty liver disease(NAFLD)are leading causes of chronic liver diseases worldwide.ALD and NAFLD encompass a broad spectrum of liver disorders ranging from simple steatosis to steatohepatitis,fibrosis,cirrhosis and superimposed hepatocellular carcinoma.Despite considerable advances in our understanding of the pathogenesis of fatty liver diseases over the past 40 years,effective diagnostic,prognostic,and therapeutic tools are still lacking.The use of animal models is crucial to investigate the cellular and molecular mechanisms underlying the development and progression of fatty liver diseases and develop novel therapeutic strategies.Although no animal model to date can faithfully replicate all the clinical and histological features of ALD or NAFLD,existing models can mimic specific aspects of human diseases.This review provides an overview of the most commonly used and recently developed rodent models of ALD and NAFLD and discusses their major strengths and shortcomings.
基金This work was supported by the National Natural Science Foundation of China(81900554)the Major Program for Sup-porting Outstanding Talents in Colleges of Ministry of Human Re-sources and Social Security of the People's Republic of Anhui(gxyqZD2020013).
文摘Alcohol-related liver disease(ALD),which is caused by excessive alcohol consumption,is one of the most common types of liver disease and a primary cause of hepatic injury,with a disease spectrum that in-cludes steatosis,steatohepatitis,fibrosis,cirrhosis,and hepatocellular carcinoma.Various lines of evi-dence have indicated that immune cells play a significant role in the inflammatory processes of ALD.On the one hand,the liver contains various resident immune cells that have been proven to perform different functions in ALD.For example,in the progression of the disease,Kupffer cells(KCs)are activated by lipopolysaccharide-Toll-like receptor 4 signaling and release various proinflammatory cytokines.Moreover,alcohol intake has been shown to depress the function of natural killer cells.Additionally,two types of unconventional T cells(natural killer T cells and mucosal-associated invariant T cells)are involved in the development of ALD.On the other hand,alcohol and many different cytokines stimulate the recruitment and infiltration of circulating immune cells(neutrophils,T cells,macrophages,and mast cells)into the liver.The neutrophils can produce proinflammatory mediators and cause the dysfunction of anti-infection processes.Additionally,alcohol intake can change the phenotype of T cells,resulting in their increased production of interleukin-17.Aside from KCs,infiltrating macrophages have also been observed in patients with ALD,but the roles of all of these cells in the progression of the disease have shown both similarities and differences.Additionally,the activated mast cells are also associated with the development of ALD.Herein,we review the diverse roles of the various immune cells in the progression of ALD.
基金supported with resources and the use of the facilities at the Omaha Veterans Affairs’Medical Center and United States Department of Veterans Affairs Merit Review grant,BX004053(to K.K.Kharbanda)and NIH grants,R01AA026723(to K.K.Kharbanda)and R01AA027189(to N.A.Osna).
文摘The review describes research findings on the influence of alcohol consumption on two crucial catabolic systems in hepatocytes:the lysosome and the ubiquitin-proteasome system(UPS).The lysosome is a membrane-bound organelle that degrades all aging and/or damaged organelles and hydrolyzes all forms of macromolecules.The UPS is mostly proteolytic.It carries out the majority of its functions in the soluble portion of the cytoplasm(cytosol)and degrades nearly all intracellular proteins,particularly those with short half-lives,so that their levels are tightly controlled.Our review will briefly discuss the epidemiology of alcohol abuse and the spectrum of alcohol-induced liver disease(AILD).We will explain why ethanol(EtOH)metabolism,but not EtOH alone,is hepatotoxic.Then,we will summarize how heavy drinking alters hepatic catabolic systems,resulting in liver enlargement that develops from hepatocyte swelling due,in part,to aberrant accumulation of undegraded lipid droplets(steatosis)and undegraded proteins(proteopathy).Our detailed description of each catabolic system will highlight its discoverer(s)and emphasize each system’s characteristics.Most important,we will review the evidence that chronic EtOH consumption disrupts hepatic lysosome biogenesis and inhibits the UPS by impeding hepatic proteasome activity.It will become evident that each of these EtOH-induced defects has far-reaching functional consequences.Finally,we will describe current and potential therapeutic interventions for alleviating EtOH-induced liver injury.The most effective intervention is the cessation of EtOH consumption.However,there are other potential approaches using natural or synthetic compounds that activate autophagy or the proteasome to enhance the degradation of accumulated lipid droplets or proteins,respectively,which could alleviate AILD.These approaches,now in their early stages of investigation,will also be discussed in this review.
基金supported by the USA National Institutes of Health(NIH)grants(R01AA023190-011P50AA024337-01,1P20GM113226-01,1U01AA026926-01,1U01AA026980-01,1U01AA022489-01A1,1R01AA023681-01)a grant from VA(1I01BX002996-01A2).
基金Portions of this work were supported by(i)a VA Merit Award(1I01BX003031,HF)from the United States Department of Veter-an's AffairsBiomedical Laboratory Research and Development Service and(ii)the R01 grant from NIH NIDDK(DK108959,HF).
文摘Alcoholic liver disease(ALD)remains one of the leading causes of liver injury and death when left un-treated.The gut microbiota has been recognized as a key regulator of a number of pathologies,including ALD.The role of mast cells(MCs)during liver disease progression has been demonstrated in a number of animal models and in human liver diseases.The interaction between the gut microbiota and MCs has been investigated,and links between the gut and these immune cells are being uncovered.The interplay between the gut microbiota and MCs during ALD has been evaluated and studies suggest that there could be an important link between MCs,their mediators and gut inflammation during the progression of ALD.
基金H.Tilg was supported by the excellence initiative(Competence Centers for Excellent Technologies-COMET)of the Austrian Research Promotion Agency(Forschungsforderungsgesellschaft,FFG):Research Center of Excellence in Vascular Ageing Tyrol,VASCage(K-Project Nr.843536)funded by the Federal Ministry for Transport,Innovation and Technology(BMVIT),Bundesministerium für Wissenschaft Forschung und Wirtschaft(BMWFW),the Wirtschaftsagentur Wien and the Standortagentur Tirol.
文摘Cytokines are considered crucial players in inflammatory-associated disorders throughout the body.Fatty liver diseases such as alcoholic liver disease(ALD)and non-alcoholic fatty liver disease(NAFLD)are commonly characterized by lipid accumulation and in a substantial subset of patients with inflammation in the liver.Amount of inflammation affects long-term outcome of liver disease including evolution of liver fibrosis,cirrhosis and hepatocellular carcinoma.Especially the pro-inflammatory cytokines Interleukin(IL)-1(αandβ)and tumor necrosis factor(TNF)αplay a central role in many stages of liver diseases mediating fundamental aspects of those diseases including acute phase protein synthesis,lipid metabolism,cholestasis and degree of fibrosis.These key cytokines released mainly by mononuclear cells affect all liver cell types and orchestrate the production of many other mediators relevant in chronic liver diseases.Inflammatory cytokines also regulate crucially the development of insulin resistance,a key component of NAFLD.Blocking these critical mediators of inflammation by specific antibodies,especially TNFα,has so far not been proven successful in alcoholic steatohepatitis,a cytokine-driven disorder.In summary,inflammatory cytokines are continuously present locally and systemically in patients with advanced fatty liver diseases,mediating and affecting the clinical phenotype and many features of these disorders.
基金This work was supported by the National Research Foundation of Korea(NRF)grant(2018R1A2A1A05077608)the Korea Mouse Phenotyping Project(2014M3A9D5A01073556)the Intelligent Synthetic Biology Center of Global Frontier Project(2011-0031955)funded by the Korea government(MSIT).
文摘Alcoholic liver disease(ALD)represents a wide spectrum of disease from simple steatosis to cirrhosis.Although there have been multiple attempts to treat ALD,its treatment is still based on abstinence from alcohol and using corticosteroids in specified cases.However,nearly 40%of patients with ALD who are in need of treatment are unresponsive to the current treatments,which implies a new paradigm shift for the treatment of ALD.Traditionally,earlier studies have focused on the abnormal metabolism occurring in the hepatocytes as a protagonist in the pathogenesis of ALD.However,increasing evidence suggests that non-parenchymal cells,such as hepatic stellate cells(HSCs),Kupffer cells,liver sinusoidal endothelial cells,and immune cells around the hepatocytes have critical roles in multiple stages of ALD either by direct or indirect cell-to-cell interactions.For instance,in the early stage of ALD,Kupffer cells and HSCs located closely to hepatocytes contribute to the development of alcoholic steatosis and inflammation through the secretion of various inflammatory cytokines(immunologic pathways)and the activation of the endocannabinoid system(metabolic pathways).While the stage of ALD progresses to alcoholic hepatitis and fibrosis,various cell-to-cell interactions with infiltrating immune cells become highly significant at the multicellular level.This review explains the diverse roles of non-parenchymal cells in the progression of ALD,as well as potential therapeutic strategies to treat ALD.
基金This work was supported by the National Natural Science Foundation of China(81873582 and 81670562 to X.Kong).
文摘Inflammation,which is mediated by leukocyte trafficking and activation,plays a prominent role in the pathogenesis of acute and chronic liver injury.Chemokines are critical mediators involved in the migration of leukocytes into the diseased liver via binding to their G protein-coupled receptors.CeC motif ligand 5(CCL5)belongs to the CC-chemokine family and is secreted by several hepatic cell pop-ulations including hepatocytes,macrophages,hepatic stellate cells,and endothelial cells upon activation.CCL5 regulates the recruitment and migration of T cells(via CCR5)and NK cells(via CCR1).Moreover,CCL5 activates and stimulates T cell proliferation and cytokine production,sequentially regulating in-flammatory responses.Accumulating studies have identified crucial effects of CCL5 both in liver-disease patients and in experimental models,in which CCL5 is elevated and displays distinct effects according to pathological conditions.In this review,we discussed the crucial functions of CCL5 in liver diseases,including acute liver failure,hepatic ischemia-reperfusion injury,acute liver failure,acute and viral hepatitis,alcoholic liver disease,non-alcoholic fatty liver disease,fibrosis,and hepatocellular carcinoma.Continued understanding the roles of CCL5 in liver disease and their mechanisms of activation are indispensable for the development of effective clinical therapeutics.
基金supported by National Institutes of Health(NIH)grants R01 AA024102-01A1(I.A.Kirpich),U01AA022489(C.J.McClain),1U01AA021901-01(C.J.McClain),1U01AA021893-01(C.J.McClain),R01AA023681(C.J.McClain)the Department of Veterans Affairs I01BX000350(C.J.McClain).Research reported in this publication was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number T35ES014559(K.H.Zirnheld)+1 种基金an Institutional Development Award(IDeA)from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM113226(C.J.McClain)the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Number P50AA024337(C.J.McClain).
文摘Alcoholic liver disease(ALD)comprises a spectrum of liver pathology,including steatosis,steatohepatitis,and cirrhosis.Previous work from our group and others suggests that dietary fat,both the amount and composition,plays a pivotal role in ALD development and progression;however,the impact of specific dietary fatty acids on ALD pathogenesis is not fully elucidated.Preclinical rodent models of ALD revealed the deleterious effects of omega-6 polyunsaturated fatty acids(n-6 PUFAs),specifically linoleic acid(LA),and this may be partially attributed to the increased levels of pro-inflammatory oxidized LA metabolites.There is limited understanding regarding the role of omega-3 polyunsaturated fatty acids(n-3 PUFAs,such as alpha-linolenic acid,eicosapentaenoic acid,and docosahexaenoic acid),and bioactive n-3 PUFAderived lipid molecules in ALD.Given that majority of n-6 and n-3 PUFAs-derived metabolites are potent endogenous signaling molecules,knowledge regarding the changes in these lipid mediators may shed new light on the mechanisms contributing to ALD pathogenesis and reveal novel therapeutic targets and biomarkers of this disease.The current review summarizes relevant scientific literature regarding the role of dietary fat,distinct fatty acids,and bioactive fatty acid metabolites in ALD,and highlights recent advances in the field.
基金The research was supported in part by the USA NIDDK DK129234,NIAAA AA026904NIGMS P20GM144269P30GM118247(to H.-M.Ni).
文摘Background:Alcohol-associated liver disease(ALD)is a major chronic liver disease around the world without successful treatment.Acute alcoholic hepatitis is one of the most severe forms of ALD with high mortality,which is often associated with binge drinking.Alcohol drinking dysregulates lipid metabolism,increases adipose tissue lipolysis,and induces liver steatosis and adipose tissue atrophy.Increasing ev-idence implicates that crosstalk of liver and adipose tissue in the pathogenesis of ALD.Mechanistic target of rapamycin(mTOR)is a phosphatidylinositol 3-kinase(PI3K)-like serine/threonine protein kinase that regulates lipid metabolism,cell proliferation and autophagy.However,the role of mTOR in regulating adipose-liver crosstalk in binge drinking-induced organ damage remains unclear.Methods:We generated liver-specific and adipocyte-specific regulatory-associated protein of mTOR(Rptor)knockout(Rptor LKO and Rptor AKO)as well as Mtor knockout(Mtor LKO and Mtor AKO)mice,by crossing Rptor flox and Mtor flox mice with albumin Cre or adiponectin Cre mice,respectively.In addition,we generated liver and adipocyte double deletion of Rptor or Mtor(Mtor LAKO and Rptor LAKO)mice.The knockout mice with their matched wild-type littermates(Rptor WT and Mtor WT)were subjected to acute gavage of 7 g/kg ethanol.Results:Mice with adipocyte deletion of Rptor or Mtor developed hepatomegaly and adipose tissue at-rophy.Alcohol gavage increased liver injury,hepatic steatosis and inflammation in mouse livers as demonstrated by elevated serum alanine aminotransferase activities,increased hepatic levels of tri-glyceride and increased hepatic numbers of CD68 positive macrophages in mouse livers after alcohol gavage.Liver injury was further exacerbated by deletion of adipocyte Rptor or Mtor.Serum adipokine array analysis revealed that increased levels of pro-inflammatory cytokines IL-6 and TNF a as well as chemokine MCP-1 following acute alcohol gavage in wild-type mice,which were further increased in adipocyte-specific Mtor or Rptor knockout mice.Conversely,levels of anti-inflammatory cytokine IL-10 decreased in adipocyte-specific Mtor or Rptor knockout mice.The levels of circulating fibroblast growth factor 21(FGF21)increased whereas levels of circulating adiponectin and fetuin A decreased in wild-type mice after alcohol gavage.Intriguingly,adipocyte-specific Mtor or Rptor knockout mice already had decreased basal level of FGF21 which increased by alcohol gavage.Moreover,adipocyte-specific Mtor or Rptor knockout mice already had increased basal level of adiponectin and decreased fetuin A which were not further changed by alcohol gavage.Conclusions:Adipocyte but not hepatocyte ablation of Mtor pathway contributes to acute alcohol-induced liver injury with increased inflammation.Our results demonstrate the critical role of adipo-cyte mTOR in regulating the adipose-liver crosstalk in ALD.