Intestinal bacteria contribute to the pathogenesis of non-alcoholic fatty liver disease(NAFLD).Recently developed microbial profiling techniques are beginning to shed light on the nature of the changes in the gut micr...Intestinal bacteria contribute to the pathogenesis of non-alcoholic fatty liver disease(NAFLD).Recently developed microbial profiling techniques are beginning to shed light on the nature of the changes in the gut microbiota that accompany NAFLD and non-alcoholic steatohepatitis(NASH).In this review,we summarize the role of gut microbiota in the development of NAFLD,NASH,and hepatocellular carcinoma(HCC).We highlight the mechanisms by which gut microbiota contribute to NAFLD/NASH,including through alterations in gut epithelial permeability,choline metabolism,endogenous alcohol production,release of inflammatory cytokines,regulation of hepatic Toll-like receptor(TLR),and bile acid metabolism.In addition,we analyze possible mechanisms for enhanced hepatic carcinogenesis,including alterations in bile acid metabolism,release of inflammatory cytokines,and expression of TLR-4.Finally,we describe therapeutic approaches for NAFLD/NASH and preventive strategies for HCC involving modulation of the intestinal microbiota or affected host pathways.Although recent studies have provided useful information,large-scale prospective studies are required to better characterize the intestinal microbiota and metabolome,in order to demonstrate a causative role for changes in the gut microbiota in the etiology of NAFLD/NASH,to identify new therapeutic strategies for NAFLD/NASH,and to develop more effective methods of preventing HCC.展开更多
Bile acids play a critical role in the regulation of glucose,lipid,and energy metabolism through activation of the nuclear bile acid receptor farnesoid X receptor(FXR)and membrane G protein-coupled bile acid receptor-...Bile acids play a critical role in the regulation of glucose,lipid,and energy metabolism through activation of the nuclear bile acid receptor farnesoid X receptor(FXR)and membrane G protein-coupled bile acid receptor-1(Gpbar-1,aka TGR5).Agonist activation of FXR and TGR5 improves insulin and glucose sensitivity and stimulates energy metabolism to prevent diabetes,obesity,and non-alcoholic fatty liver disease(NAFLD).Bile acids have both pro-and anti-inflammatory actions through FXR and TGR5 in the intestine and liver.In the intestine,bile acids activate FXR and TGR5 to stimulate fibroblast growth factor 15 and glucagon-like peptide-1 secretion.FXR and TGR5 agonists may have therapeutic potential for treating liver-related metabolic diseases,such as diabetes and NAFLD.展开更多
Bile acids modulate several gastrointestinal(GI)functions including electrolyte secretion and absorption,gastric emptying,and small intestinal and colonic motility.High concentrations of bile acids lead to diarrhea an...Bile acids modulate several gastrointestinal(GI)functions including electrolyte secretion and absorption,gastric emptying,and small intestinal and colonic motility.High concentrations of bile acids lead to diarrhea and are implicated in the development of esophageal,gastric and colonic cancer.Alterations in bile acid homeostasis are also implicated in the pathophysiology of irritable bowel syndrome(IBS)and inflammatory bowel disease(IBD).Our understanding of the mechanisms underlying these effects of bile acids on gut functions has been greatly enhanced by the discovery of bile acid receptors,including the nuclear receptors:farnesoid X receptor(FXR),vitamin D receptor(VDR),pregnane X receptor(PXR),and constitutive androstane receptor(CAR);and G protein-coupled receptors(GPCRs):Takeda G protein-coupled receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and muscarinic acetylcholine receptor M3(M3R).For example,various studies provided evidence demonstrating the anti-inflammatory effects of FXR and TGR5 activation in models of intestinal inflammation.In addition,the activation of TGR5 in enteric neurons was recently shown to increase colonic motility,which may lead to bile acid-induced diarrhea(BAD).Interestingly,TGR5 induces the secretion of glucagon-like peptide-1(GLP-1)from L-cells to enhance insulin secretion and modulate glucose metabolism.Because of the importance of these receptors,agonists of TGR5 and intestine-specific FXR agonists are currently being tested as an option for the treatment of diabetes mellitus and primary bile acid diarrhea,respectively.This review summarizes current knowledge of the functional roles of bile acid receptors in the GI tract.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
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
Liver cancer is the sixth most common cancer worldwide,and the third most common cause of cancer-related death.Hepatocellular carcinoma(HCC),which accounts for more than 90%of primary liver cancers,is an important pub...Liver cancer is the sixth most common cancer worldwide,and the third most common cause of cancer-related death.Hepatocellular carcinoma(HCC),which accounts for more than 90%of primary liver cancers,is an important public health problem.In addition to cirrhosis caused by hepatitis B viral(HBV)or hepatitis C viral(HCV)infection,non-alcoholic fatty liver disease(NAFLD)is becoming a major risk factor for liver cancer because of the prevalence of obesity.Non-alcoholic steatohepatitis(NASH)will likely become the leading indication for liver transplantation in the future.It is well recognized that gut microbiota is a key environmental factor in the pathogenesis of liver disease and cancer.The interplay between gut microbiota and liver disease has been investigated in animal and clinical studies.In this article,we summarize the roles of gut microbiota in the development of liver disease as well as gut microbiota-targeted therapies.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
Mitophagy(mitochondrial autophagy)in hepatocytes is an essential quality control mechanism that removes for lysosomal digestion damaged,effete and superfluous mitochondria.Mitophagy has distinct variants.In type 1 mit...Mitophagy(mitochondrial autophagy)in hepatocytes is an essential quality control mechanism that removes for lysosomal digestion damaged,effete and superfluous mitochondria.Mitophagy has distinct variants.In type 1 mitophagy,typical of nutrient deprivation,cup-shaped sequestration membranes(phagophores)grow,surround and sequester individual mitochondria into mitophagosomes,often in coordination with mitochondrial fission.After sequestration,the outer compartment of the mitophagosome acidifies and the entrapped mitochondrion depolarizes,followed by fusion with lysosomes.By contrast,mitochondrial depolarization stimulates type 2 mitophagy,which is characterized by coalescence of autophagic microtubule-associated protein 1A/1B-light chain 3(LC3)-containing structures on mitochondrial surfaces without the formation of a phagophore or mitochondrial fission.Oppositely to type 1 mitophagy,the inhibition of phosphoinositide-3-kinase(PI3K)does not block type 2 mitophagy.In type 3 mitophagy,or micromitophagy,mitochondria-derived vesicles(MDVs)enriched in oxidized proteins bud off from mitochondrial inner and outer membranes and incorporate into multivesicular bodies by vesicle scission into the lumen.In response to ethanol feeding,widespread ethanol-induced hepatocellular mitochondrial depolarization occurs to facilitate hepatic ethanol metabolism.As a consequence,type 2 mitophagy develops in response to the mitochondrial depolarization.After chronic high ethanol feeding,processing of depolarized mitochondria by mitophagy becomes compromised,leading to release of mitochondrial damage-associated molecular patterns(mtDAMPs)that promote inflammatory and profibrogenic responses.We propose that the persistence of mitochondrial responses for acute ethanol metabolism links initial adaptive ethanol metabolism to mitophagy and then to chronic maladaptive changes initiating onset and the progression of alcoholic liver disease(ALD).展开更多
Non-alcoholic fatty liver disease(NAFLD)is a chronic progressive liver disorder that begins with simple hepatic steatosis and progresses to non-alcoholic steatohepatitis,fibrosis,cirrhosis,and even liver cancer.As the...Non-alcoholic fatty liver disease(NAFLD)is a chronic progressive liver disorder that begins with simple hepatic steatosis and progresses to non-alcoholic steatohepatitis,fibrosis,cirrhosis,and even liver cancer.As the global prevalence of NAFLD rises,it is increasingly important that we understand its pathogenesis and develop effective therapies for this chronic disease.Forkhead box O(FOXO)transcription factors are key downstream regulators in the insulin/insulin-like growth factor 1(IGF1)signaling pathway,and have been implicated in a range of cellular functions including the regulation of glucose,triglyceride,and cholesterol homeostasis.The role of FOXOs in the modulation of immune response and inflammation is complex,with reports of both pro-and anti-inflammatory effects.FOXOs are reported to protect against hepatic fibrosis by inhibiting proliferation and transdifferentiation of hepatic stellate cells.Mice that are deficient in hepatic FOXOs are more susceptible to non-alcoholic steatohepatitis than wild-type controls.In summary,FOXOs play a critical role in maintaining metabolic and cellular homeostasis in the liver,and dysregulation of FOXOs may be involved in the NAFLD development.展开更多
Hepatocellular carcinoma(HCC)is one of the most common malignant tumors with a low survival rate.The identification of mechanisms underlying the development of HCC helps uncover cellular and mo-lecular targets for the...Hepatocellular carcinoma(HCC)is one of the most common malignant tumors with a low survival rate.The identification of mechanisms underlying the development of HCC helps uncover cellular and mo-lecular targets for the diagnosis,prevention,and treatment of HCC.Golgi protein 73(GP73)level is up-regulated in HCC patients and potentially can be a therapeutic target.Despite many studies devoted to GP73 as a marker for HCC early diagnosis,there is little discussion about the function of GP73 in HCC tumorigenesis.Given the poor response to currently available HCC therapies,a better understanding of the role of GP73 in HCC may provide a new therapeutic target for HCC.The current paper summarizes the role of GP73 as a diagnostic marker as well as its roles in liver carcinogenesis.Its roles in other types of cancer are also discussed.展开更多
Galectins(Gals)are evolutionarily conserved proteins that bind to b-galactoside containing glycans.Abnormal expression of Gals is associated with the development,progression,and metastasis of different types of cancer...Galectins(Gals)are evolutionarily conserved proteins that bind to b-galactoside containing glycans.Abnormal expression of Gals is associated with the development,progression,and metastasis of different types of cancer.Among the 11 Gals identified in humans,the roles of Gal-1 and Gal-3 have been extensively investigated in various tumors.Here,we summarize the roles of overly expressed Gal-1 and Gal-3 in the pathogenesis of hepatocellular carcinoma(HCC).The overexpression of Gal-1 and Gal-3 correlates with tumor growth,HCC cell migration and invasion,tumor aggressiveness,metastasis,and poor prognosis.A potentially promising future treatment strategy for HCC may include the combination of immunotherapy with Gal-1 inhibition.Additional research is warranted to investigate targeting Gal-1 and Gal-3 for HCC treatment.展开更多
Background and aim:Overdose of acetaminophen(APAP)leads to liver injury,which is one of the most common causes of liver failure in the United States.We previously demonstrated that pharmacological activation of autoph...Background and aim:Overdose of acetaminophen(APAP)leads to liver injury,which is one of the most common causes of liver failure in the United States.We previously demonstrated that pharmacological activation of autophagy protects against APAP-induced liver injury in mice via removal of damaged mitochondria and APAP-adducts(APAP-ADs).Using an image-based high-throughput screening for autophagy modulators,we recently identified that chlorpromazine(CPZ),a dopamine inhibitor used for anti-schizophrenia,is a potent autophagy inducer in vitro.Therefore,the aim of the present study is to determine whether CPZ may protect against APAP-induced liver injury via inducing autophagy.Methods:Wild type C57BL/6J mice were injected with APAP to induce liver injury.CPZ was administrated either at the same time with APAP(co-treatment)or 2 h later after APAP administration(post-treat-ment).Hemotoxyline and eosin(H&E)staining of liver histology,terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling(TUNEL)staining of necrotic cell death as well as serum levels of alanine aminotransferase(ALT)were used to monitor liver injury.Results:We found that CPZ markedly protected against APAP-induced liver injury as demonstrated by decreased serum levels of ALT,liver necrotic areas as well as TUNEL-positive cells in mice that were either co-treated or post-treated with CPZ.Mechanistically,we observed that CPZ increased the number of autolysosomes and decreased APAP-induced c-Jun N-terminal kinase activation without affecting the metabolic activation of APAP.Pharmacological inhibition of autophagy by chloroquine partially weak-ened the protective effects of CPZ against APAP-induced liver injury.Conclusions:Our results indicate that CPZ ameliorates APAP-induced liver injury partially via activating hepatic autophagy and inhibiting JNK activation.展开更多
The liver is one of the major metabolic organs in the body,playing a critical role in the metabolism of carbohydrates,proteins,amino acids,lipids,drugs and xenobiotics.As a result,the liver often becomes the target of...The liver is one of the major metabolic organs in the body,playing a critical role in the metabolism of carbohydrates,proteins,amino acids,lipids,drugs and xenobiotics.As a result,the liver often becomes the target of drug and xenobiotics-induced damage.Currently,the most common cause for acute liver failure in the United States and multiple European countries is drug-induced liver injury(DILI).This is one of the leading causes for halting drug development and removing drugs from the consumer market.展开更多
Fatty liver diseases,non-alcoholic fatty liver disease(NAFLD)and alcoholic liver disease(ALD)are the most common causes of chronic liver diseases around the world.NAFLD and ALD can progress towards a more severe form ...Fatty liver diseases,non-alcoholic fatty liver disease(NAFLD)and alcoholic liver disease(ALD)are the most common causes of chronic liver diseases around the world.NAFLD and ALD can progress towards a more severe form of the disease,including as non-alcoholic steatohepatitis(NASH)and alcoholic steatohepatitis(ASH).In both instances central pathogenic events include hepatocyte death,liver inflammation,pathological angiogenesis,and fibrosis,followed by cirrhosis and cancer.Over the last few years,extracellular vesicles(EVs)have been identified as effective cell-to-cell communicators that contain a cell-and stressspecific cargo from the cell of origin and are capable of transferring this cargo to a target or acceptor cell.In this review,we focus on the growing evidence supporting a role for EVs in the pathophysiology of NASH and ASH as well as their potential roles as targets for novel biomarkers for these conditions.展开更多
Many receptors can be activated by bile acids(BAs)and their derivatives.These include nuclear receptors farnesoid X receptor(FXR),pregnane X receptor(PXR),and vitamin D receptor(VDR),as well as membrane receptors Take...Many receptors can be activated by bile acids(BAs)and their derivatives.These include nuclear receptors farnesoid X receptor(FXR),pregnane X receptor(PXR),and vitamin D receptor(VDR),as well as membrane receptors Takeda G protein receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cholinergic receptor muscarinic 2(CHRM2).All of them are implicated in the development of metabolic and immunological diseases in response to endobiotic and xenobiotic exposure.Because epigenetic regulation is critical for organisms to adapt to constant environmental changes,this review article summarizes epigenetic regulation as well as post-transcriptional modification of bile acid re-ceptors.In addition,the focus of this review is on the liver and digestive tract although these receptors may have effects on other organs.Those regulatory mechanisms are implicated in the disease process and critically important in uncovering innovative strategy for prevention and treatment of metabolic and immunological diseases.展开更多
Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1...Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1 a(IRE1 a),double-stranded RNA-dependent protein kinase(PKR)-like ER kinase(PERK)and activating transcription factor 6(ATF6)signaling pathways,is a protective cellular response activated by ER stress.However,UPR activation can also induce cell death upon persistent ER stress.The liver is susceptible to ER stress given its synthetic and other biological functions.Numerous studies from human liver samples and animal disease models have indicated a crucial role of ER stress and the UPR signaling pathways in the pathogenesis of liver diseases,including non-alcoholic fatty liver disease(NAFLD),alcoholic liver disease(ALD),alpha-1 antitrypsin(AAT)deficiency(AATD),cholestatic liver disease,drug-induced liver injury,ischemia/reperfusion(I/R)injury,viral hepatitis and hepatocel-lular carcinoma(HCC).Extensive investigations have demonstrated the potential underlying mechanisms of the induction of ER stress and the contribution of the UPR pathways during the development of the diseases.Moreover,ER stress and the UPR proteins and genes have become emerging therapeutic targets to treat liver diseases.展开更多
Sarcopenia and physical deconditioning are common complications in patients with liver cancer,which are frequently caused by insufficient physical activity and poor nutritional status,resulting in physical frailty and...Sarcopenia and physical deconditioning are common complications in patients with liver cancer,which are frequently caused by insufficient physical activity and poor nutritional status,resulting in physical frailty and a significant impact on the patient's physical fitness.Notably,sarcopenia,frailty,and poor cardiopulmonary endurance have all been linked to higher mortality rates among patients with liver cancer.Exercise intervention significantly improves various health parameters in liver cancer patients,including metabolic syndrome,muscle wasting,cardiorespiratory endurance,health-related quality of life,and reduction in hepatic venous pressure gradient.However,the link between physical exercise and liver cancer is commonly overlooked.In this article,we will examine the impact of exercise on liver cancer and present the most recent evidence on the best types of exercise for various stages of liver cancer.This article also summarizes and discusses the molecular mechanisms that control metabolism and systemic immune function in tumors.In brief,physical exercise should be considered an important intervention in the prevention and treatment of liver cancer and its complications.展开更多
Hepatitis E is a globally distributed infection that varies in seroprevalence between developed and developing regions.In the less developed regions of Asia and Africa,a high seropositivity rate has been reported for ...Hepatitis E is a globally distributed infection that varies in seroprevalence between developed and developing regions.In the less developed regions of Asia and Africa,a high seropositivity rate has been reported for hepatitis E virus(HEV)antibodies.Although acute hepatitis E is often self-limited and has a favorable prognosis,some populations experience severe manifestations,which may progress to liver failure.Moreover,some immunocompromised patients are at risk of developing chronic HEV infection and cirrhosis.Proactive screening,reducing misdiagnosis,improving patient management,timely anti-viral therapy for severe and chronic cases,and vaccination of high-risk groups are important measures to reduce the morbidity of hepatitis E.This review focused on the clinical presentation,management,and prevention of hepatitis E.展开更多
The liver has a strong regenerative capacity that ensures patient recovery after hepatectomy and liver transplantation.The portal system plays a crucial role in the dual blood supply to the liver,making it a significa...The liver has a strong regenerative capacity that ensures patient recovery after hepatectomy and liver transplantation.The portal system plays a crucial role in the dual blood supply to the liver,making it a significant factor in hepatic function.Several surgical strategies,such as portal vein ligation,associating liver partition and portal vein ligation for staged hepatectomy,and dual vein embolization,have high-lighted the portal system's importance in liver regeneration.Following hepatectomy or liver trans-plantation,the hemodynamic properties of the portal system change dramatically,triggering regeneration via shear stress and the induction of hypoxia.However,excessive portal hyperperfusion can harm the liver and negatively affect patient outcomes.Furthermore,as the importance of the gut-liver axis has gradually been revealed,the effect of metabolites and cytokines from gut microbes carried by portal blood on liver regeneration has been acknowledged.From these perspectives,this review outlines the molecular mechanisms of the portal system's role in liver regeneration and summarizes therapeutic strategies based on the portal system intervention to promote liver regeneration.展开更多
The liver possesses an extraordinary ability to regenerate after injury.Hepatocyte-driven liver regeneration is the default pathway in response to mild-to-moderate acute liver damage.When replication of mature hepatoc...The liver possesses an extraordinary ability to regenerate after injury.Hepatocyte-driven liver regeneration is the default pathway in response to mild-to-moderate acute liver damage.When replication of mature hepatocytes is blocked,facultative hepatic progenitor cells(HPCs),also referred to as oval cells(OCs)in rodents,are activated.HPC/OCs have the ability to proliferate clonogenically and differentiate into several lineages including hepatocytes and bile ductal epithelia.This is a conserved liver injury response that has been studied in many species ranging from mammals(rat,mouse,and human)to fish.In addition,improper HPC/OC activation is closely associated with fibrotic responses,characterized by myofibroblast activation and extracellular matrix production,in many chronic liver diseases.Matrix remodeling and metalloprotease activities play an important role in the regulation of HPC/OC proliferation and fibrosis progression.Thus,understanding molecular mechanisms underlying HPC/OC activation has therapeutic implications for rational design of anti-fibrotic therapies.展开更多
基金This study was supported by the USA National Institutes of Health(NIH)grant R01 AA020703,and by Award Number I01BX002213 from the Biomedical Laboratory Research&Development Service of the VA Office of Research and Development to B.Schnab.
文摘Intestinal bacteria contribute to the pathogenesis of non-alcoholic fatty liver disease(NAFLD).Recently developed microbial profiling techniques are beginning to shed light on the nature of the changes in the gut microbiota that accompany NAFLD and non-alcoholic steatohepatitis(NASH).In this review,we summarize the role of gut microbiota in the development of NAFLD,NASH,and hepatocellular carcinoma(HCC).We highlight the mechanisms by which gut microbiota contribute to NAFLD/NASH,including through alterations in gut epithelial permeability,choline metabolism,endogenous alcohol production,release of inflammatory cytokines,regulation of hepatic Toll-like receptor(TLR),and bile acid metabolism.In addition,we analyze possible mechanisms for enhanced hepatic carcinogenesis,including alterations in bile acid metabolism,release of inflammatory cytokines,and expression of TLR-4.Finally,we describe therapeutic approaches for NAFLD/NASH and preventive strategies for HCC involving modulation of the intestinal microbiota or affected host pathways.Although recent studies have provided useful information,large-scale prospective studies are required to better characterize the intestinal microbiota and metabolome,in order to demonstrate a causative role for changes in the gut microbiota in the etiology of NAFLD/NASH,to identify new therapeutic strategies for NAFLD/NASH,and to develop more effective methods of preventing HCC.
基金This work was supported by US National Institutes of Health grants DK44442 and DK58379.
文摘Bile acids play a critical role in the regulation of glucose,lipid,and energy metabolism through activation of the nuclear bile acid receptor farnesoid X receptor(FXR)and membrane G protein-coupled bile acid receptor-1(Gpbar-1,aka TGR5).Agonist activation of FXR and TGR5 improves insulin and glucose sensitivity and stimulates energy metabolism to prevent diabetes,obesity,and non-alcoholic fatty liver disease(NAFLD).Bile acids have both pro-and anti-inflammatory actions through FXR and TGR5 in the intestine and liver.In the intestine,bile acids activate FXR and TGR5 to stimulate fibroblast growth factor 15 and glucagon-like peptide-1 secretion.FXR and TGR5 agonists may have therapeutic potential for treating liver-related metabolic diseases,such as diabetes and NAFLD.
基金The work in the authors'laboratories was supported by merit review grants from the Department of Veterans Affairs,United States(VA):BX000152(W.A.Alrefai)and BX002011(P.K.Dudeja)F30 grant DK117535(A.L.Ticho)and R01 grants:DK109709(W.A.Alrefai),DK54016(P.K.Dudeja),DK81858(P.K.Dudeja),DK92441(P.K.Dudeja),DK98170(R.K.Gill),from the USA National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health,United States.
文摘Bile acids modulate several gastrointestinal(GI)functions including electrolyte secretion and absorption,gastric emptying,and small intestinal and colonic motility.High concentrations of bile acids lead to diarrhea and are implicated in the development of esophageal,gastric and colonic cancer.Alterations in bile acid homeostasis are also implicated in the pathophysiology of irritable bowel syndrome(IBS)and inflammatory bowel disease(IBD).Our understanding of the mechanisms underlying these effects of bile acids on gut functions has been greatly enhanced by the discovery of bile acid receptors,including the nuclear receptors:farnesoid X receptor(FXR),vitamin D receptor(VDR),pregnane X receptor(PXR),and constitutive androstane receptor(CAR);and G protein-coupled receptors(GPCRs):Takeda G protein-coupled receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and muscarinic acetylcholine receptor M3(M3R).For example,various studies provided evidence demonstrating the anti-inflammatory effects of FXR and TGR5 activation in models of intestinal inflammation.In addition,the activation of TGR5 in enteric neurons was recently shown to increase colonic motility,which may lead to bile acid-induced diarrhea(BAD).Interestingly,TGR5 induces the secretion of glucagon-like peptide-1(GLP-1)from L-cells to enhance insulin secretion and modulate glucose metabolism.Because of the importance of these receptors,agonists of TGR5 and intestine-specific FXR agonists are currently being tested as an option for the treatment of diabetes mellitus and primary bile acid diarrhea,respectively.This review summarizes current knowledge of the functional roles of bile acid receptors in the GI tract.
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 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Liver cancer is the sixth most common cancer worldwide,and the third most common cause of cancer-related death.Hepatocellular carcinoma(HCC),which accounts for more than 90%of primary liver cancers,is an important public health problem.In addition to cirrhosis caused by hepatitis B viral(HBV)or hepatitis C viral(HCV)infection,non-alcoholic fatty liver disease(NAFLD)is becoming a major risk factor for liver cancer because of the prevalence of obesity.Non-alcoholic steatohepatitis(NASH)will likely become the leading indication for liver transplantation in the future.It is well recognized that gut microbiota is a key environmental factor in the pathogenesis of liver disease and cancer.The interplay between gut microbiota and liver disease has been investigated in animal and clinical studies.In this article,we summarize the roles of gut microbiota in the development of liver disease as well as gut microbiota-targeted therapies.
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.
基金This work was supported,in part,by Grants AA025379,AA021191,AA022815,and DK073336 from the USA National Institutes of Health(NIH).Imaging facilities were supported,in part,by P30 CA138313 and 1S10OD018113.
文摘Mitophagy(mitochondrial autophagy)in hepatocytes is an essential quality control mechanism that removes for lysosomal digestion damaged,effete and superfluous mitochondria.Mitophagy has distinct variants.In type 1 mitophagy,typical of nutrient deprivation,cup-shaped sequestration membranes(phagophores)grow,surround and sequester individual mitochondria into mitophagosomes,often in coordination with mitochondrial fission.After sequestration,the outer compartment of the mitophagosome acidifies and the entrapped mitochondrion depolarizes,followed by fusion with lysosomes.By contrast,mitochondrial depolarization stimulates type 2 mitophagy,which is characterized by coalescence of autophagic microtubule-associated protein 1A/1B-light chain 3(LC3)-containing structures on mitochondrial surfaces without the formation of a phagophore or mitochondrial fission.Oppositely to type 1 mitophagy,the inhibition of phosphoinositide-3-kinase(PI3K)does not block type 2 mitophagy.In type 3 mitophagy,or micromitophagy,mitochondria-derived vesicles(MDVs)enriched in oxidized proteins bud off from mitochondrial inner and outer membranes and incorporate into multivesicular bodies by vesicle scission into the lumen.In response to ethanol feeding,widespread ethanol-induced hepatocellular mitochondrial depolarization occurs to facilitate hepatic ethanol metabolism.As a consequence,type 2 mitophagy develops in response to the mitochondrial depolarization.After chronic high ethanol feeding,processing of depolarized mitochondria by mitophagy becomes compromised,leading to release of mitochondrial damage-associated molecular patterns(mtDAMPs)that promote inflammatory and profibrogenic responses.We propose that the persistence of mitochondrial responses for acute ethanol metabolism links initial adaptive ethanol metabolism to mitophagy and then to chronic maladaptive changes initiating onset and the progression of alcoholic liver disease(ALD).
基金This work was supported in part by the USA National Institutes of Health(NIH)grants including DK091592 and DK107682 from the National Institute of Diabetes and Digestive and Kidney Diseases and AA024550 from the National Institute on Alcohol Abuse and Alcoholism,by the Showalter Scholar award from Indiana University School of Medicine and Showalter Trust,and by Indiana Clinical and Translational Sciences Institute grant ULITR001108 from the NIH National Center for Advancing Translational Sciences,Clinical and Translational Sciences Award.
文摘Non-alcoholic fatty liver disease(NAFLD)is a chronic progressive liver disorder that begins with simple hepatic steatosis and progresses to non-alcoholic steatohepatitis,fibrosis,cirrhosis,and even liver cancer.As the global prevalence of NAFLD rises,it is increasingly important that we understand its pathogenesis and develop effective therapies for this chronic disease.Forkhead box O(FOXO)transcription factors are key downstream regulators in the insulin/insulin-like growth factor 1(IGF1)signaling pathway,and have been implicated in a range of cellular functions including the regulation of glucose,triglyceride,and cholesterol homeostasis.The role of FOXOs in the modulation of immune response and inflammation is complex,with reports of both pro-and anti-inflammatory effects.FOXOs are reported to protect against hepatic fibrosis by inhibiting proliferation and transdifferentiation of hepatic stellate cells.Mice that are deficient in hepatic FOXOs are more susceptible to non-alcoholic steatohepatitis than wild-type controls.In summary,FOXOs play a critical role in maintaining metabolic and cellular homeostasis in the liver,and dysregulation of FOXOs may be involved in the NAFLD development.
基金This study was supported bygrants funded by the USA National Institutes of Health(NIH)R01CA222490 to Y.-J.Y.Wanalong with grants from the National Natural Science Foundation of China Project number 81602456financial sup-port from the China Scholarship Council(CSC)to Y.Wang.
文摘Hepatocellular carcinoma(HCC)is one of the most common malignant tumors with a low survival rate.The identification of mechanisms underlying the development of HCC helps uncover cellular and mo-lecular targets for the diagnosis,prevention,and treatment of HCC.Golgi protein 73(GP73)level is up-regulated in HCC patients and potentially can be a therapeutic target.Despite many studies devoted to GP73 as a marker for HCC early diagnosis,there is little discussion about the function of GP73 in HCC tumorigenesis.Given the poor response to currently available HCC therapies,a better understanding of the role of GP73 in HCC may provide a new therapeutic target for HCC.The current paper summarizes the role of GP73 as a diagnostic marker as well as its roles in liver carcinogenesis.Its roles in other types of cancer are also discussed.
基金This manuscript is supported by grants funded by the USA National Institutes of Health(NIH)U01CA179582,R01CA222490,T32 CA108459-15UC Davis Comprehensive Cancer Center seed grant.
文摘Galectins(Gals)are evolutionarily conserved proteins that bind to b-galactoside containing glycans.Abnormal expression of Gals is associated with the development,progression,and metastasis of different types of cancer.Among the 11 Gals identified in humans,the roles of Gal-1 and Gal-3 have been extensively investigated in various tumors.Here,we summarize the roles of overly expressed Gal-1 and Gal-3 in the pathogenesis of hepatocellular carcinoma(HCC).The overexpression of Gal-1 and Gal-3 correlates with tumor growth,HCC cell migration and invasion,tumor aggressiveness,metastasis,and poor prognosis.A potentially promising future treatment strategy for HCC may include the combination of immunotherapy with Gal-1 inhibition.Additional research is warranted to investigate targeting Gal-1 and Gal-3 for HCC treatment.
基金This research was funded by the USA NIH R01 AA 020518,R01 DK 102142,U01 AA 024733,P20 GM 103549(COBRE),and P30 GM 118247(COBRE)。
文摘Background and aim:Overdose of acetaminophen(APAP)leads to liver injury,which is one of the most common causes of liver failure in the United States.We previously demonstrated that pharmacological activation of autophagy protects against APAP-induced liver injury in mice via removal of damaged mitochondria and APAP-adducts(APAP-ADs).Using an image-based high-throughput screening for autophagy modulators,we recently identified that chlorpromazine(CPZ),a dopamine inhibitor used for anti-schizophrenia,is a potent autophagy inducer in vitro.Therefore,the aim of the present study is to determine whether CPZ may protect against APAP-induced liver injury via inducing autophagy.Methods:Wild type C57BL/6J mice were injected with APAP to induce liver injury.CPZ was administrated either at the same time with APAP(co-treatment)or 2 h later after APAP administration(post-treat-ment).Hemotoxyline and eosin(H&E)staining of liver histology,terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling(TUNEL)staining of necrotic cell death as well as serum levels of alanine aminotransferase(ALT)were used to monitor liver injury.Results:We found that CPZ markedly protected against APAP-induced liver injury as demonstrated by decreased serum levels of ALT,liver necrotic areas as well as TUNEL-positive cells in mice that were either co-treated or post-treated with CPZ.Mechanistically,we observed that CPZ increased the number of autolysosomes and decreased APAP-induced c-Jun N-terminal kinase activation without affecting the metabolic activation of APAP.Pharmacological inhibition of autophagy by chloroquine partially weak-ened the protective effects of CPZ against APAP-induced liver injury.Conclusions:Our results indicate that CPZ ameliorates APAP-induced liver injury partially via activating hepatic autophagy and inhibiting JNK activation.
基金The research was supported in part by the USA NIAAA R37 AA020518,U01 AA024733,R21 AA027250 and NIDDK R01 DK102142(W.-X.Ding).
文摘The liver is one of the major metabolic organs in the body,playing a critical role in the metabolism of carbohydrates,proteins,amino acids,lipids,drugs and xenobiotics.As a result,the liver often becomes the target of drug and xenobiotics-induced damage.Currently,the most common cause for acute liver failure in the United States and multiple European countries is drug-induced liver injury(DILI).This is one of the leading causes for halting drug development and removing drugs from the consumer market.
基金This work was partially supported by the USA National Institutes Health(NIH)grants U01 AA022489 to A.E.Feldstein and R21 AA023574 to A.Eguchi and A.E.Feldstein.
文摘Fatty liver diseases,non-alcoholic fatty liver disease(NAFLD)and alcoholic liver disease(ALD)are the most common causes of chronic liver diseases around the world.NAFLD and ALD can progress towards a more severe form of the disease,including as non-alcoholic steatohepatitis(NASH)and alcoholic steatohepatitis(ASH).In both instances central pathogenic events include hepatocyte death,liver inflammation,pathological angiogenesis,and fibrosis,followed by cirrhosis and cancer.Over the last few years,extracellular vesicles(EVs)have been identified as effective cell-to-cell communicators that contain a cell-and stressspecific cargo from the cell of origin and are capable of transferring this cargo to a target or acceptor cell.In this review,we focus on the growing evidence supporting a role for EVs in the pathophysiology of NASH and ASH as well as their potential roles as targets for novel biomarkers for these conditions.
基金This study was supported by grants funded by the USA National Institutes of Health(NIH)U01CA179582 and R01 CA222490.
文摘Many receptors can be activated by bile acids(BAs)and their derivatives.These include nuclear receptors farnesoid X receptor(FXR),pregnane X receptor(PXR),and vitamin D receptor(VDR),as well as membrane receptors Takeda G protein receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cholinergic receptor muscarinic 2(CHRM2).All of them are implicated in the development of metabolic and immunological diseases in response to endobiotic and xenobiotic exposure.Because epigenetic regulation is critical for organisms to adapt to constant environmental changes,this review article summarizes epigenetic regulation as well as post-transcriptional modification of bile acid re-ceptors.In addition,the focus of this review is on the liver and digestive tract although these receptors may have effects on other organs.Those regulatory mechanisms are implicated in the disease process and critically important in uncovering innovative strategy for prevention and treatment of metabolic and immunological diseases.
基金This work was supported by USA National Institute of Diabetes and Digestive and Kidney Diseases(NIDDK)R01 DK093807.
文摘Endoplasmic reticulum(ER)stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion.The unfolded protein response(UPR),comprising of inositol-requiring enzyme 1 a(IRE1 a),double-stranded RNA-dependent protein kinase(PKR)-like ER kinase(PERK)and activating transcription factor 6(ATF6)signaling pathways,is a protective cellular response activated by ER stress.However,UPR activation can also induce cell death upon persistent ER stress.The liver is susceptible to ER stress given its synthetic and other biological functions.Numerous studies from human liver samples and animal disease models have indicated a crucial role of ER stress and the UPR signaling pathways in the pathogenesis of liver diseases,including non-alcoholic fatty liver disease(NAFLD),alcoholic liver disease(ALD),alpha-1 antitrypsin(AAT)deficiency(AATD),cholestatic liver disease,drug-induced liver injury,ischemia/reperfusion(I/R)injury,viral hepatitis and hepatocel-lular carcinoma(HCC).Extensive investigations have demonstrated the potential underlying mechanisms of the induction of ER stress and the contribution of the UPR pathways during the development of the diseases.Moreover,ER stress and the UPR proteins and genes have become emerging therapeutic targets to treat liver diseases.
基金supported by grants from Top Talent Support Program for young and middle-aged people of Wuxi Health Committee(No.BJ2023049,China)Wuxi Social Development Science and Technology Demonstration Project(No.20201003,China).
文摘Sarcopenia and physical deconditioning are common complications in patients with liver cancer,which are frequently caused by insufficient physical activity and poor nutritional status,resulting in physical frailty and a significant impact on the patient's physical fitness.Notably,sarcopenia,frailty,and poor cardiopulmonary endurance have all been linked to higher mortality rates among patients with liver cancer.Exercise intervention significantly improves various health parameters in liver cancer patients,including metabolic syndrome,muscle wasting,cardiorespiratory endurance,health-related quality of life,and reduction in hepatic venous pressure gradient.However,the link between physical exercise and liver cancer is commonly overlooked.In this article,we will examine the impact of exercise on liver cancer and present the most recent evidence on the best types of exercise for various stages of liver cancer.This article also summarizes and discusses the molecular mechanisms that control metabolism and systemic immune function in tumors.In brief,physical exercise should be considered an important intervention in the prevention and treatment of liver cancer and its complications.
基金supported by grants from the Natural Science Foundation of China(No.82070611)Natural Science Foundation of Guangdong Province(2020A1515010317)+5 种基金Guangdong Basic and Applied Basic Research Foundation(No.21202104030000608 and 2021A1515220029)Guangzhou Science and Technology Plan Projects(No.202102010204 and 2023B03J1287)Guangzhou Science and Technology Program Key Projects(No.2023B01J1007)Sun Yat-sen University Clinical Research 5010 Program(No.2020007 and 2018009)Transformation of Scientific and Technological Achievements Project of Sun Yat-sen University(No.82000-18843236)the Five-Year Plan of the Third Affliated Hospital of Sun Yat-sen University(No.K00006 and P02421).
文摘Hepatitis E is a globally distributed infection that varies in seroprevalence between developed and developing regions.In the less developed regions of Asia and Africa,a high seropositivity rate has been reported for hepatitis E virus(HEV)antibodies.Although acute hepatitis E is often self-limited and has a favorable prognosis,some populations experience severe manifestations,which may progress to liver failure.Moreover,some immunocompromised patients are at risk of developing chronic HEV infection and cirrhosis.Proactive screening,reducing misdiagnosis,improving patient management,timely anti-viral therapy for severe and chronic cases,and vaccination of high-risk groups are important measures to reduce the morbidity of hepatitis E.This review focused on the clinical presentation,management,and prevention of hepatitis E.
基金supported by The National Key Research and Development Program of China(No.2021 YFA1100504)Key Program,National Natural Science Foundation of China(No.81930016)The Zhejiang Provincial Natural Science Foundation(LY22H160048).
文摘The liver has a strong regenerative capacity that ensures patient recovery after hepatectomy and liver transplantation.The portal system plays a crucial role in the dual blood supply to the liver,making it a significant factor in hepatic function.Several surgical strategies,such as portal vein ligation,associating liver partition and portal vein ligation for staged hepatectomy,and dual vein embolization,have high-lighted the portal system's importance in liver regeneration.Following hepatectomy or liver trans-plantation,the hemodynamic properties of the portal system change dramatically,triggering regeneration via shear stress and the induction of hypoxia.However,excessive portal hyperperfusion can harm the liver and negatively affect patient outcomes.Furthermore,as the importance of the gut-liver axis has gradually been revealed,the effect of metabolites and cytokines from gut microbes carried by portal blood on liver regeneration has been acknowledged.From these perspectives,this review outlines the molecular mechanisms of the portal system's role in liver regeneration and summarizes therapeutic strategies based on the portal system intervention to promote liver regeneration.
文摘The liver possesses an extraordinary ability to regenerate after injury.Hepatocyte-driven liver regeneration is the default pathway in response to mild-to-moderate acute liver damage.When replication of mature hepatocytes is blocked,facultative hepatic progenitor cells(HPCs),also referred to as oval cells(OCs)in rodents,are activated.HPC/OCs have the ability to proliferate clonogenically and differentiate into several lineages including hepatocytes and bile ductal epithelia.This is a conserved liver injury response that has been studied in many species ranging from mammals(rat,mouse,and human)to fish.In addition,improper HPC/OC activation is closely associated with fibrotic responses,characterized by myofibroblast activation and extracellular matrix production,in many chronic liver diseases.Matrix remodeling and metalloprotease activities play an important role in the regulation of HPC/OC proliferation and fibrosis progression.Thus,understanding molecular mechanisms underlying HPC/OC activation has therapeutic implications for rational design of anti-fibrotic therapies.
