Metabolic dysfunction and alcohol-associated liver disease(MetALD)is a recently implemented nomenclature and disease terminology for patients with metabolic dysfunction-associated steatotic liver disease,who consume g...Metabolic dysfunction and alcohol-associated liver disease(MetALD)is a recently implemented nomenclature and disease terminology for patients with metabolic dysfunction-associated steatotic liver disease,who consume greater amounts of alcohol.MetALD is diagnosed in individuals who have at least one metabolic risk factor(such as obesity,type 2 diabetes mellitus,hypertension,etc)and consume 140–350 g/week of alcohol for women or 210–420 g/week for men.Conversely,alcohol-associated liver disease is diagnosed in individuals who consume>350 g/week of alcohol for women and>420 g/week for men.MetALD represents a heterogeneous spectrum of liver disease,with variations in clinical presentation and severity driven by differences in metabolic profiles,drinking patterns and individual susceptibility.Alcohol and metabolic risk factors are thought to act synergistically to accelerate steatohepatitis,fibrosis and hepatocellular carcinoma.However,the precise mechanisms underlying liver injury in MetALD still remain poorly understood.In this comprehensive review,we summarise the current definition,diagnostic criteria and clinical management of MetALD.We also discuss emerging insights into understanding its pathogenesis,examine relevant experimental models and highlight future challenges and research priorities in this evolving field.展开更多
Metabolic dysfunction-associated steatohepatitis(MASH),a severe type of metabolic dysfunction-associated steatotic liver disease(MASLD),is a leading etiology of end-stage liver disease worldwide,posing significant hea...Metabolic dysfunction-associated steatohepatitis(MASH),a severe type of metabolic dysfunction-associated steatotic liver disease(MASLD),is a leading etiology of end-stage liver disease worldwide,posing significant health and economic burdens.microRNA-320(miR-320),a ubiquitously expressed and evolutionarily conserved miRNA,has been reported to regulate lipid metabolism;however,whether and how miR-320 affects MASH development remains unclear.By performing miR-320 in situ hybridization with RNAscope,we observed a notable downregulation of miR-320 in hepatocytes during MASH,correlating with disease severity.Most importantly,miR-320 downregulation in hepatocytes exacerbated MASH progression as demonstrated that hepatocyte-specific miR-320 deficient mice were more susceptible to high-fat,high-fructose,high-cholesterol diet(HFHC)or choline-deficient,amino acid-defined,high-fat diet(CDAHFD)-induced MASH compared with control littermates.Conversely,restoration of miR-320 in hepatocytes ameliorated MASH-related steatosis and fibrosis by injection of adeno-associated virus 8(AAV8)carrying miR-320 in different types of diet-induced MASH models.Mechanistic studies revealed that miR-320 specifically regulated fibroblast growth factor 1(FGF1)production in hepatocytes by inhibiting regulator factor X1(RFX1)expression.Notably,knockdown of Rfx1in hepatocytes mitigated MASH by enhancing FGF1-mediated AMPK activation.Our findings underscore the therapeutic potential of hepatic miR-320 supplementation in MASH treatment by inhibiting RFX1-mediated FGF1 suppression.展开更多
Chronic liver injury with any etiology can progress to fibrosis and the end-stage diseases cirrhosis and hepatocellular carcinoma.The progression of liver disease is controlled by a variety of factors,including liver ...Chronic liver injury with any etiology can progress to fibrosis and the end-stage diseases cirrhosis and hepatocellular carcinoma.The progression of liver disease is controlled by a variety of factors,including liver injury,inflammatory cells,inflammatory mediators,cytokines,and the gut microbiome.In the current review,we discuss recent data on a large number of cytokines that play important roles in regulating liver injury,inflammation,fibrosis,and regeneration,with a focus on interferons and T helper(Th)1,Th2,Th9,Th17,interleukin(IL)-1 family,IL-6 family,and IL-20 family cytokines.Hepatocytes can also produce certain cytokines(such as IL-7,IL-11;and IL-33),and the functions of these cytokines in the liver are briefly summarized.Several cytokines have great therapeutic potential,and some are currently being tested as therapeutic targets in clinical trials for the treatment of liver diseases,which are also described.展开更多
Non-alcoholic fatty liver disease(NAFLD)is characterized by a spectrum of hepatic diseases,including fatty liver,non-alcoholic steatohepatitis,cirrhosis,and hepatocellular carcinoma.NAFLD is a hepatic manifestation of...Non-alcoholic fatty liver disease(NAFLD)is characterized by a spectrum of hepatic diseases,including fatty liver,non-alcoholic steatohepatitis,cirrhosis,and hepatocellular carcinoma.NAFLD is a hepatic manifestation of metabolic syndrome and has become the leading cause of liver transplantation,necessitating an in-depth understanding of its underlying pathogenic mechanisms and the identification of viable drug targets.Although fatty liver is benign and does not exert marked liver damage or inflammation,NAFLD progression involves inflammatory processes facilitated by immune cells.Macrophages and monocytes constitute the pool of innate immune cells that contribute to NAFLD development in association with other cell types,such as neutrophils,T cells,and natural killer cells.The concept that macrophages contribute to the inflammatory processes in NAFLD development has long been debated;however,the remarkable advances in experimental techniques have rapidly uncovered new subpopulations of macrophages and monocytes,whose functions need to be comprehensively elucidated.The current review focuses on the recent expansion of our knowledge of the heterogeneous population of macrophages crucially involved in NAFLD development.In addition,the present paper discusses ongoing efforts to target macrophages and inflammatory processes to develop optimal therapeutic agents against non-alcoholic steatohepatitis.展开更多
基金supported in part by the intramural programme of the NIAAA(BG)and the NIAAA/NIDA(LL)SL is supported in part by U01 AA026917,UH2/UH3 AA026903,R01 AA030312 and the Department of Veterans Affairs Merit Award 1I01 CX000361 and I01 BX006202,and by the Dean’s Scholar Award from Indiana University School of Medicine+6 种基金W-XD is supported by R37 AA020518,R21 AA030617 and R01 AA031230GS is supported by R01 AA032418 and R56 AA017729BS is supported by NIH grants P30 DK120515 and P50 AA011999CL is supported by R01 AA029106 and R21 AA030654RL receives funding support from UL1 TR001442,U01 DK061734,U01 DK130190,R01 DK121378,P30 DK120515,P01 HL147835 and the John C Martin Foundation(RP124)FT is supported by the German Research Foundation(DFG CRC/TR 412,Project-ID 535081457 and SFB1382,Project-ID 403224013)under Germany's Excellence Strategy-EXC 3118/1-project number 533770413.
文摘Metabolic dysfunction and alcohol-associated liver disease(MetALD)is a recently implemented nomenclature and disease terminology for patients with metabolic dysfunction-associated steatotic liver disease,who consume greater amounts of alcohol.MetALD is diagnosed in individuals who have at least one metabolic risk factor(such as obesity,type 2 diabetes mellitus,hypertension,etc)and consume 140–350 g/week of alcohol for women or 210–420 g/week for men.Conversely,alcohol-associated liver disease is diagnosed in individuals who consume>350 g/week of alcohol for women and>420 g/week for men.MetALD represents a heterogeneous spectrum of liver disease,with variations in clinical presentation and severity driven by differences in metabolic profiles,drinking patterns and individual susceptibility.Alcohol and metabolic risk factors are thought to act synergistically to accelerate steatohepatitis,fibrosis and hepatocellular carcinoma.However,the precise mechanisms underlying liver injury in MetALD still remain poorly understood.In this comprehensive review,we summarise the current definition,diagnostic criteria and clinical management of MetALD.We also discuss emerging insights into understanding its pathogenesis,examine relevant experimental models and highlight future challenges and research priorities in this evolving field.
基金supported by the National Natural Science Foundation of China(82300657 and 82270601)the National Key Research and Development Program of China(2023YFA1800804)the Natural Science Foundation of Shanghai(22ZR1473800,China).
文摘Metabolic dysfunction-associated steatohepatitis(MASH),a severe type of metabolic dysfunction-associated steatotic liver disease(MASLD),is a leading etiology of end-stage liver disease worldwide,posing significant health and economic burdens.microRNA-320(miR-320),a ubiquitously expressed and evolutionarily conserved miRNA,has been reported to regulate lipid metabolism;however,whether and how miR-320 affects MASH development remains unclear.By performing miR-320 in situ hybridization with RNAscope,we observed a notable downregulation of miR-320 in hepatocytes during MASH,correlating with disease severity.Most importantly,miR-320 downregulation in hepatocytes exacerbated MASH progression as demonstrated that hepatocyte-specific miR-320 deficient mice were more susceptible to high-fat,high-fructose,high-cholesterol diet(HFHC)or choline-deficient,amino acid-defined,high-fat diet(CDAHFD)-induced MASH compared with control littermates.Conversely,restoration of miR-320 in hepatocytes ameliorated MASH-related steatosis and fibrosis by injection of adeno-associated virus 8(AAV8)carrying miR-320 in different types of diet-induced MASH models.Mechanistic studies revealed that miR-320 specifically regulated fibroblast growth factor 1(FGF1)production in hepatocytes by inhibiting regulator factor X1(RFX1)expression.Notably,knockdown of Rfx1in hepatocytes mitigated MASH by enhancing FGF1-mediated AMPK activation.Our findings underscore the therapeutic potential of hepatic miR-320 supplementation in MASH treatment by inhibiting RFX1-mediated FGF1 suppression.
基金supported by the intramural program of the NIAAA(Bin Gao),U01 AA022614,and R01 DK099205(Tatiana Kisseleva)and AA011576 and AA017729(Gyongyi Szabo).
文摘Chronic liver injury with any etiology can progress to fibrosis and the end-stage diseases cirrhosis and hepatocellular carcinoma.The progression of liver disease is controlled by a variety of factors,including liver injury,inflammatory cells,inflammatory mediators,cytokines,and the gut microbiome.In the current review,we discuss recent data on a large number of cytokines that play important roles in regulating liver injury,inflammation,fibrosis,and regeneration,with a focus on interferons and T helper(Th)1,Th2,Th9,Th17,interleukin(IL)-1 family,IL-6 family,and IL-20 family cytokines.Hepatocytes can also produce certain cytokines(such as IL-7,IL-11;and IL-33),and the functions of these cytokines in the liver are briefly summarized.Several cytokines have great therapeutic potential,and some are currently being tested as therapeutic targets in clinical trials for the treatment of liver diseases,which are also described.
基金supported by a 2-Year Research Grant of Pusan National University of Korea to S.Hwang.
文摘Non-alcoholic fatty liver disease(NAFLD)is characterized by a spectrum of hepatic diseases,including fatty liver,non-alcoholic steatohepatitis,cirrhosis,and hepatocellular carcinoma.NAFLD is a hepatic manifestation of metabolic syndrome and has become the leading cause of liver transplantation,necessitating an in-depth understanding of its underlying pathogenic mechanisms and the identification of viable drug targets.Although fatty liver is benign and does not exert marked liver damage or inflammation,NAFLD progression involves inflammatory processes facilitated by immune cells.Macrophages and monocytes constitute the pool of innate immune cells that contribute to NAFLD development in association with other cell types,such as neutrophils,T cells,and natural killer cells.The concept that macrophages contribute to the inflammatory processes in NAFLD development has long been debated;however,the remarkable advances in experimental techniques have rapidly uncovered new subpopulations of macrophages and monocytes,whose functions need to be comprehensively elucidated.The current review focuses on the recent expansion of our knowledge of the heterogeneous population of macrophages crucially involved in NAFLD development.In addition,the present paper discusses ongoing efforts to target macrophages and inflammatory processes to develop optimal therapeutic agents against non-alcoholic steatohepatitis.
