Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD)has emerged as a predominant cause of chronic liver disease globally,with its prevalence rising steadily each year.If left untreated,MASLD may progress to...Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD)has emerged as a predominant cause of chronic liver disease globally,with its prevalence rising steadily each year.If left untreated,MASLD may progress to metabolic dysfunction in associated steatohepatitis(MASH),a more severe condition that can irreversibly advance to liver fibrosis,cirrhosis,and even hepatocyte carcinoma(HCC).Recent studies have illuminated a pivotal link between dysregulated cholesterol metabolism and the pathogenesis and severity of MASLD.This underscores the critical need for a comprehensive exploration of the regulatory mechanisms underlying hepatic cholesterol metabolism in MASLD,as such insights could unveil new therapeutic targets and pave the way for early diagnosis and effective prevention strategies.Cyclocarya paliurus(Batal.)Iljinskaja,a plant known for both medicinal and dietary applications,has demonstrated diverse pharmacological properties,including hypoglycemic,lipid-regulating,and hepatoprotective effects.This study aimed to investigate the hypolipidemic and hepatoprotective activities of Cyclocarya paliurus extract(CCE)in a murine model of MASLD induced by a methionine-choline-deficient(MCD)diet.Simvastatin was employed as a positive control drug,while various doses of CCE were administered to assess its therapeutic potential.Meanwhile,the control and model groups received 0.5%sodium carboxymethyl cellulose(CMC-Na)once daily for 6 weeks.At the end of the treatment period,blood and liver samples were collected for biochemical analysis,histopathological assessment,and gene expression profiling.The findings revealed that CCE significantly reduced serum levels of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)while enhancing the activities of cholinesterase(CHE)and high-density lipoprotein cholesterol(HDL-C).In liver tissues,CCE markedly decreased the levels of total cholesterol(TC)and triglycerides(TG),while simultaneously increasing hepatic HDL-C content.Histological analyses showed notable alleviation of pathological liver damage in CCE-treated mice.Molecular studies further demonstrated that CCE downregulated the expression of key genes and proteins involved in cholesterol synthesis,including SREBP2,LDLR,and HMGCR.Concurrently,it upregulated the expression of genes and proteins related to cholesterol transport,such as ABCG5 and ABCG8.Additionally,CCE mitigated inflammation by improving the expression levels of pro-inflammatory cytokines,including TNF-α and IL-6,and modulated oxidative stress markers,such as NRF2,KEAP1,and NQO1.Protein expression analyses revealed reduced levels of IL-6 and IL-1β,further corroborating its anti-inflammatory effects.In summary,C.paliurus exhibited potent hepatoprotective effects in MCD-induced MASLD mice.These protective mechanisms were closely linked to the upregulation of cholesterol transporters ABCG5/8 and the modulation of sterol regulatory element-binding protein 2(SREBP2).This study highlighted the therapeutic potential of C.paliurus as a promising intervention for MASLD and underscored its role in regulating cholesterol metabolism and mitigating inflammation and oxidative stress.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD),previously known as nonalcoholic fatty liver disease(NAFLD),is the most prevalent chronic liver disease worldwide,with an estimated global prevalence of ...Metabolic dysfunction-associated steatotic liver disease(MASLD),previously known as nonalcoholic fatty liver disease(NAFLD),is the most prevalent chronic liver disease worldwide,with an estimated global prevalence of approximately 30%;however,effective pharmacotherapies are still limited due to its complex pathogenesis and etiology.Therefore,a more thorough understanding of disease pathogenesis is urgently needed.An increasing number of studies suggest that MASLD and its progressive form,metabolic dysfunction-associated steatohepatitis(MASH),are driven by chronic overnutrition,multiple genetic susceptibility factors,and pathogenic consequences,including hepatocyte damage and liver inflammation.Hepatic inflammation is the key event fueling the conversion from simple steatosis to steatohepatitis and fibrosis.Current therapies for MASH,including the recently approved thyroid hormone receptor-beta agonist resmetirom or the available incretin mimetics,mainly target metabolic injury to the liver but not inflammation directly.In this review,we provide an in-depth discussion of current data related to the immunological mechanisms of MASLD and summarize the effects of current and experimental therapies on immunoregulation in MASLD.展开更多
Aims:The synergistic impact of alcohol consumption and cardiometabolic risk factors(CMRFs)on liver health remains unclear.Herein,we aimed to investigate the interplay between varying levels of alcohol consumption and ...Aims:The synergistic impact of alcohol consumption and cardiometabolic risk factors(CMRFs)on liver health remains unclear.Herein,we aimed to investigate the interplay between varying levels of alcohol consumption and the number of CMRFs on all-cause mortality in individuals with metabolic dysfunction-associated steatotic liver disease(MASLD)and metabolic and alcohol-associated liver disease(MetALD).Methods:Adult participants with ultrasound-proven hepatic steatosis were identified using the Third National Health and Nutrition Examination Survey(NHANES III)database.Multivariate Cox regression was applied to investigate the association between incremental alcohol consumption and the number of CMRFs,with all-cause mortality as the outcome.The E-value was calculated to assess the robustness of the associations,and additive interaction models were used to explore the synergistic effects of alcohol consumption and CMRFs on mortality.Results:A total of 2161 individuals(1957 with MASLD and 204 with MetALD)between the Years 1988 and 1994 were included in the analysis.During a follow-up period of 51,719 person-years,the overall mortality rate was 1.46%per person-year.Stratification by age showed an increased mortality risk associated with CMRFs and alcohol consumption in individuals aged<65 years,especially among those with 3-5 CMRFs(hazard ratio:3.15-5.71,all p<0.05).Additive interaction models also supported a synergistic effect in this subgroup,while no such trend was observed in those aged≥65 years.Conclusion:Among individuals with MASLD/MetALD and MASLD alone,a significant synergistic effect between alcohol consumption and CMRFs on mortality risk was found in those aged<65 years.This suggests an age-stratified approach for managing modifiable risk factors in individuals with MASLD or MetALD.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD),the most prevalent chronic liver condition globally,lacks adequate and effective therapeutic remedies in clinical practice.Recent studies have increasing...Metabolic dysfunction-associated steatotic liver disease(MASLD),the most prevalent chronic liver condition globally,lacks adequate and effective therapeutic remedies in clinical practice.Recent studies have increasingly highlighted the close connection between the ubiquitin–proteasome system(UPS)and the progression of MASLD.This relationship is crucial for understanding the disease's underlying mechanism.As a sophisticated process,the UPS govern protein stability and function,maintaining protein homeostasis,thus influencing a multitude of elements and biological events of eukaryotic cells.It comprises four enzyme families,namely,ubiquitin-activating enzymes(E1),ubiquitin-conjugating enzymes(E2),ubiquitin-protein ligases(E3),and deubiquitinating enzymes(DUBs).This review aims to delve into the array of pathways and therapeutic targets implicated in the ubiquitination within the pathogenesis of MASLD.Therefore,this review unveils the role of ubiquitination in MASLD while spotlighting potential therapeutic targets within the context of this disease.展开更多
The new European clinical practice guidelines from three scientific societies(European Association for the Study of the Liver,European Association for the Study of Diabetes and European Association for the Study of Ob...The new European clinical practice guidelines from three scientific societies(European Association for the Study of the Liver,European Association for the Study of Diabetes and European Association for the Study of Obesity)on the management of metabolic dysfunction-associated steatotic liver disease(MASLD)provide detailed recommendations on diagnosis,risk stratification,monitoring strategies,treatment and prevention.Lifestyle interventions(eg,weight reduction,Mediterranean diet,exercise,alcohol abstinence)and the treatment of cardiometabolic risk factors continue to be the mainstay of treatment and prevention of the disease.Incretin mimetics that are approved to treat obesity and/or type 2 diabetes such as semaglutide and tirzepatide have benefits for ameliorating metabolic dysfunction-associated steatohepatitis(MASH).Novel developments include adapted strategies for screening(case finding)using non-invasive tests(NITs)with a focus on detecting fibrosis or cirrhosis,risk-adjusted monitoring of MASLD by NITs as well as the recommendation to use,if locally approved,the thyroid hormone receptorβ-agonist resmetirom in patients with non-cirrhotic MASH fibrosis(≥F2 stage).展开更多
Background Metabolic dysfunction-associated steatotic liver disease(MASLD)is the leading cause of chronic liver disease globally,with rising prevalence linked to metabolic syndrome(MetS).Excessive liver fat accumulati...Background Metabolic dysfunction-associated steatotic liver disease(MASLD)is the leading cause of chronic liver disease globally,with rising prevalence linked to metabolic syndrome(MetS).Excessive liver fat accumulation(steatosis)worsens disease progression and MASLD prognosis.Moreover,gut microbiota dysbiosis might promote steatosis,accelerating the disease progression to severe stages.Identifying gut microbiota signatures specific to steatosis severity might improve its diagnosis and inform personalised interventions in MASLD.This study aimed to characterise associations between gut microbiota composition and hepatic steatosis severity in a cohort of patients with MASLD/MetS.Ultimately,we aimed to assess the potential for microbiota features to enhance the diagnosis of severe steatosis.Methods A cross-sectional cohort of 61 patients with MetS with extensive clinical history was recruited at different stages of MASLD.Transient elastography was used to evaluate liver fibrosis and steatosis severity.Participants’faecal microbiota were profiled using 16S rRNA gene sequencing.Statistical analyses first identified correlations between microbiota profiles and patients’phenotypes,while disentangling important confounders such as medication.Identified features were then used to build predictive models for diagnosing severe steatosis.Results High steatosis severity was distinctly associated with a higher prevalence of the inflammation-associated Bacteroides 2(Bact2)-enterotype,accompanied by a lower proportion of beneficial commensals(eg,Akkermansia)and a higher proportion of opportunistic bacteria(eg,Streptococcus).Patients harbouring a Bact2-enterotype reached severe steatosis at lower Fatty Liver Index(FLI)thresholds.Using Bact2-carrier status together with FLI in a predictive model significantly improved the classification of severe steatosis(accuracy 90%,receiver operating characteristics 96%)when compared with FLI alone.Conclusion Gut microbiota composition and dysbiosis(defined as Bact2-enterotype)are distinctly associated with steatosis severity in MASLD/MetS.Patient stratification by microbiota composition enhances the diagnostic classification of severe steatosis in MASLD,suggesting a potential for personalised interventions in patients with microbiota dysbiosis.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)is a global health burden that requires early screening,diagnosis,and intervention MASLD is a leading cause of chronic liver disease globally,with an esti...Metabolic dysfunction-associated steatotic liver disease(MASLD)is a global health burden that requires early screening,diagnosis,and intervention MASLD is a leading cause of chronic liver disease globally,with an estimated prevalence of 38%worldwide(1,2).MASLD is the new term that replaces what was previously known as non-alcoholic fatty liver disease(NAFLD).展开更多
The prevalence of cirrhosis and hepatocellular carcinoma resulting from metabolic dysfunction-associated steatotic liver disease(MASLD)is increasing,posing a significant burden on both the economy and public health(1,...The prevalence of cirrhosis and hepatocellular carcinoma resulting from metabolic dysfunction-associated steatotic liver disease(MASLD)is increasing,posing a significant burden on both the economy and public health(1,2).Although the need for effective therapeutic strategies for MASLD is growing,pharmacologic options remain limited,with resmetirom currently the only approved drug.Consequently,lifestyle modification-particularly weight reduction through diet and exercise-remains the cornerstone of MASLD management.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)remains a rapidly growing global health burden.Here,we report that the nonessential amino acid(NEAA)transporter SLC7A11 plays a key role in MASLD.In patie...Metabolic dysfunction-associated steatotic liver disease(MASLD)remains a rapidly growing global health burden.Here,we report that the nonessential amino acid(NEAA)transporter SLC7A11 plays a key role in MASLD.In patients with MASLD,we found high expression levels of SLC7A11 that were correlated directly with clinical grade.Using both loss-of-function and gain-of-function genetic models,we found that Slc7a11 deficiency accelerated MASLD progression via classic cystine/cysteine deficiencyinduced ferroptosis,while serine deficiency and a resulting impairment in de novo cysteine production were attributed to ferroptosis-induced MASLD progression in mice overexpressing hepatic Slc7a11.Consistent with these findings,we found that both serine supplementation and blocking ferroptosis significantly alleviated MASLD,and the serum serine/glutamate ratio was significantly lower in these preclinical disease models,suggesting that it might serve as a prognostic biomarker for MASLD in patients.These findings indicate that defects in NEAA metabolism are involved in the progression of MASLD and that serine deficiency-triggered ferroptosis may provide a therapeutic target for its treatment.展开更多
In the present narrative review,we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease(NAFLD)/metabolic dysfunction-associated steatotic liver disease(MASLD).We start by revi...In the present narrative review,we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease(NAFLD)/metabolic dysfunction-associated steatotic liver disease(MASLD).We start by reviewing the epidemiology of the condition and its close association with obesity and type 2 diabetes.We then discuss how randomized-controlled trials are performed following guidance from regulatory agencies,including differences and similarities between requirements of the US Food and Drug Administration and the European Medicine Agency.Difficulties and hurdles related to limitations of liver biopsy,a large number of screening failures in recruiting patients,as well as unpredictable response rates in the placebo group are evaluated.Finally,we recapitulate the strategies employed for potential drug treatments of this orphan condition.The first is to repurpose drugs that originally targeted T2DM and/or obesity,such as pioglitazone,glucagon-like peptide 1 receptor agonists(liraglutide and semaglutide),multi-agonists(tirzepatide and retatrutide),and sodium-glucose transporter 2 inhibitors.The second is to develop drugs specifically targeting NAFLD/MASLD.Among those,we focused on resmetirom,fibroblast growth factor 21 analogs,and lanifibranor,as they are currently in Phase 3 of their clinical trial development.While many failures have characterized the field of pharmacological treatment of NAFLD/MASLD in the past,it is likely that approval of the first treatments is near.As occurs in many chronic conditions,combination therapy might lead to better outcomes.In the case of non-alcoholic steatohepatitis,we speculate that drugs treating underlying metabolic co-morbidities might play a bigger role in the earlier stages of disease,while liver-targeting molecules will become vital in patients with more advanced disease in terms of inflammation and fibrosis.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis(MASH),cirrhosis,and cancer.The zonal distribution of biomolec...Metabolic dysfunction-associated steatotic liver disease(MASLD)is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis(MASH),cirrhosis,and cancer.The zonal distribution of biomolecules in the liver is implicated in mediat-ing the disease progression.Recently,G-protein-coupled receptor 35(GPR35)has been highlighted to play a role in MASLD,but the precise mechanism is not fully understood,particularly,in a liver-zonal manner.Here,we aimed to identify spatially distributed specific genes and metabolites in different liver zonation that are regulated by GPR35 in MASLD,by combining lipid metabolomics,spatial transcriptomics(ST),and spatial metabolomics(SM).We found that GPR35 influenced lipid accumulation,inflammatory and metabolism-related factors in specific regions,notably affecting the anti-inflammation factor ELF4(E74 like E-twenty six(ETS)tran-scription factor 4),lipid homeostasis key factor CIDEA(cell death-inducing DNA fragmentation factor alpha(DFFA)-like effector A),and the injury response-related genes SAA1/2/3(serum amyloid A1/2/3),thereby impacting MASLD progression.Furthermore,SM elucidated specific metabolite distributions across different liver regions,such as C10H11N4O7P(3ʹ,5ʹ-cyclic inosine monophosphate(3ʹ,5ʹ-IMP))for the central vein,and this metabolite significantly decreased in the liver zones of GPR35-deficient mice during MASLD progression.Taken together,GPR35 regulates hepatocyte damage repair,controls inflammation,and prevents MASLD progression by influencing phospholipid homeostasis and gene expression in a zonal manner.展开更多
My invited commentary discusses a recent paper published by Ebrahimi et al.[28].To this end,the definitions of nonalcoholic fatty liver disease(NAFLD),metabolic dysfunction-associated fatty liver disease(MAFLD),and th...My invited commentary discusses a recent paper published by Ebrahimi et al.[28].To this end,the definitions of nonalcoholic fatty liver disease(NAFLD),metabolic dysfunction-associated fatty liver disease(MAFLD),and the most recently proposed metabolic dysfunction-associated steatotic liver disease(MASLD)are reviewed.For brevity,the overarching definition of metabolic fatty liver syndromes(MFLS)is utilized to allude to NAFLD/MAFLD/MASLD collectively,although each nomenclature identifies different diagnostic criteria and distinct patient populations.Ebrahimi and colleagues conducted an analysis using data from the National Swedish Multigeneration archive,involving 38,018 MASLD first-degree relatives(FDRs)and 9,381 MASLD spouses,alongside 197,303 comparator FDRs and 47,572 comparator spouses.These authors followed these groups for a median of 17.6 years and reported a definite familial aggregation of adverse liver-related events among families of MASLD individuals.These events comprise increased relative risks of hepatocellular carcinoma(HCC),major chronic liver disease,and mortality owing to hepatic causes.I comment on this study with reference to the ongoing changes in terminology describing MFLS and to sexual dimorphism exhibited by MFLS.It is concluded that the study by Ebrahimi adds another piece to the puzzle of knowledge requested to implement those precision medicine approaches that are eagerly awaited in the field of MFLS.展开更多
Aim:Hepatocellular carcinoma(HCC)in patients with Metabolic dysfunction-associated steatotic liver disease(MASLD,formerly NAFLD)is expected to be a significant public health issue in the near future.Therefore,understa...Aim:Hepatocellular carcinoma(HCC)in patients with Metabolic dysfunction-associated steatotic liver disease(MASLD,formerly NAFLD)is expected to be a significant public health issue in the near future.Therefore,understanding the tumor microenvironment interactions in MASLD-induced HCC is crucial,and the development of relevant preclinical models is needed.Hence,we aimed to determine the effects of a MASLD-mimicking microenvironment(ME)on the aggressiveness of HCC cells and identify target genes that drive HCC by developing a 3D-in vitro co-culture system.Methods:A 3D co-culture system mimicking the MASLD-ME was created with LX-2 liver stellate cells embedded in 3D collagen gel in the lower and SNU-449 HCC cells on the upper parts of Boyden chambers,and cells were grown in an optimized metabolic medium(MM).The effects of MASLD-ME on motility,sphere formation,proliferation,and cell cycle of SNU-449 cells were tested by Boyden chamber,3D sphere formation,XTT,and Flow cytometry,respectively.The protein expression/activation profiles of motile SNU-449 cells that passed the membrane toward MASLD-ME or control condition were investigated using a multiplex protein profiling system DigiWest and confirmed with RT-PCR,WB,and Flow cytometry.IDH2 levels were examined in primary human HCC and adjacent liver tissues by IHC and in TCGA and CPTAC cohorts by bioinformatics tools.Results:MM treatment increased fat accumulation,motility,and spheroid formation of both SNU-449 and LX-2 cells.MASLD-ME induced activation of LX2 cells,leading to the formation of bigger colonies with many intrusions compared to related controls.DigiWest analysis showed that metabolism-related proteins such as IDH2 were the most affected molecules in SNU-449 cells that migrated toward the MASLD-ME compared to those that migrated toward the control condition.Downregulation of IDH2 expression was confirmed in SNU-449 cells grown in MASLD-ME,in primary HCC tumor samples by IHC,and in HCC patient cohorts by bioinformatics analysis.Conclusion:This study reports the potential involvement of MASLD-ME in the downregulation of IDH2 expression and promoted motility and colonization capacity of HCC cells.The 3D MASLD model presented in this study may be useful in investigating the mechanistic roles of MASLD-ME in HCC.展开更多
目的探究血浆致动脉粥样硬化指数(atherogenic index of plasma,AIP)与代谢功能障碍相关脂肪性肝病(metabolism-associated steatotic liver disease,MASLD)的关系,评估AIP作为MASLD风险预测指标的潜在价值,为早期预防和临床干预提供参...目的探究血浆致动脉粥样硬化指数(atherogenic index of plasma,AIP)与代谢功能障碍相关脂肪性肝病(metabolism-associated steatotic liver disease,MASLD)的关系,评估AIP作为MASLD风险预测指标的潜在价值,为早期预防和临床干预提供参考。方法纳入2021年6月至2023年5月西安交通大学第二附属医院4850名健康体检者。按AIP四分位数将全体受试者由低到高分为4组(Q1~Q4),比较各组间生化指标与MASLD患病率。采用Logistic回归、亚组分析、限制性立方样条(restricted cubic splines,RCS)等方法探究AIP与MASLD之间的相关性。结果共纳入4850例受试者,MASLD患病率为26.08%(1265例)。Q1~Q4组MASLD的患病率分别为4.0%、13.8%、30.8%、55.6%,患病率随AIP四分位数组级升高而呈显著递增趋势(P<0.001)。与Q1组相比,Q2~Q4组男性占比、身体质量指数(body mass index,BMI)、吸烟者占比、超重肥胖占比、腹型肥胖占比、糖尿病前期占比、高血压占比、血尿酸及脂肪肝指数(fatty liver index,FLI)水平均明显增加,差异有统计学意义(P<0.001)。随着AIP的增加,血清总胆固醇、三酰甘油、低密度脂蛋白胆固醇水平显著增加,高密度脂蛋白胆固醇水平则显著降低(P<0.001)。RCS曲线显示随着AIP增加,MASLD的患病风险显著增加,AIP与MASLD患病风险之间呈线性关系。Logistic回归显示,在调整混杂因素后,Q4组中MASLD发生风险为Q1组的8.71倍(OR=8.71,95%CI:6.20~12.23,P<0.001)。建立的复合模型具有更高的判别性能(AUC=0.883,95%CI:0.873~0.892)。交互作用分析提示AIP与BMI、高血压及糖尿病前期存在显著交互作用(P<0.05),在无上述代谢异常的人群中,AIP与MASLD的关联更为显著。结论AIP升高与MASLD发病风险增加显著相关,尤其在BMI正常组、血压正常组及血糖正常组中关联更强,提示AIP有望作为MASLD早期筛查的潜在指标。展开更多
基金National Key Research and Development Program of China(Grant No.2022YFC3501700)the Beijing Municipal Natural Science Foundation(Grant No.7144219).
文摘Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD)has emerged as a predominant cause of chronic liver disease globally,with its prevalence rising steadily each year.If left untreated,MASLD may progress to metabolic dysfunction in associated steatohepatitis(MASH),a more severe condition that can irreversibly advance to liver fibrosis,cirrhosis,and even hepatocyte carcinoma(HCC).Recent studies have illuminated a pivotal link between dysregulated cholesterol metabolism and the pathogenesis and severity of MASLD.This underscores the critical need for a comprehensive exploration of the regulatory mechanisms underlying hepatic cholesterol metabolism in MASLD,as such insights could unveil new therapeutic targets and pave the way for early diagnosis and effective prevention strategies.Cyclocarya paliurus(Batal.)Iljinskaja,a plant known for both medicinal and dietary applications,has demonstrated diverse pharmacological properties,including hypoglycemic,lipid-regulating,and hepatoprotective effects.This study aimed to investigate the hypolipidemic and hepatoprotective activities of Cyclocarya paliurus extract(CCE)in a murine model of MASLD induced by a methionine-choline-deficient(MCD)diet.Simvastatin was employed as a positive control drug,while various doses of CCE were administered to assess its therapeutic potential.Meanwhile,the control and model groups received 0.5%sodium carboxymethyl cellulose(CMC-Na)once daily for 6 weeks.At the end of the treatment period,blood and liver samples were collected for biochemical analysis,histopathological assessment,and gene expression profiling.The findings revealed that CCE significantly reduced serum levels of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)while enhancing the activities of cholinesterase(CHE)and high-density lipoprotein cholesterol(HDL-C).In liver tissues,CCE markedly decreased the levels of total cholesterol(TC)and triglycerides(TG),while simultaneously increasing hepatic HDL-C content.Histological analyses showed notable alleviation of pathological liver damage in CCE-treated mice.Molecular studies further demonstrated that CCE downregulated the expression of key genes and proteins involved in cholesterol synthesis,including SREBP2,LDLR,and HMGCR.Concurrently,it upregulated the expression of genes and proteins related to cholesterol transport,such as ABCG5 and ABCG8.Additionally,CCE mitigated inflammation by improving the expression levels of pro-inflammatory cytokines,including TNF-α and IL-6,and modulated oxidative stress markers,such as NRF2,KEAP1,and NQO1.Protein expression analyses revealed reduced levels of IL-6 and IL-1β,further corroborating its anti-inflammatory effects.In summary,C.paliurus exhibited potent hepatoprotective effects in MCD-induced MASLD mice.These protective mechanisms were closely linked to the upregulation of cholesterol transporters ABCG5/8 and the modulation of sterol regulatory element-binding protein 2(SREBP2).This study highlighted the therapeutic potential of C.paliurus as a promising intervention for MASLD and underscored its role in regulating cholesterol metabolism and mitigating inflammation and oxidative stress.
基金sponsored by the National Science and Technology Innovation 2030 Major Program(2024ZD0530604)the National Key Research and Development Program of China(2023YFA1800804)+2 种基金the National Natural Science Foundation of China(82270601,China)the German Research Foundation(DFG Ta434/8-1 and SFB1382,Project-ID 403224013)the U.S.National Institutes of Health(R01DK137061 and R01DK133930 to D.D.).
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD),previously known as nonalcoholic fatty liver disease(NAFLD),is the most prevalent chronic liver disease worldwide,with an estimated global prevalence of approximately 30%;however,effective pharmacotherapies are still limited due to its complex pathogenesis and etiology.Therefore,a more thorough understanding of disease pathogenesis is urgently needed.An increasing number of studies suggest that MASLD and its progressive form,metabolic dysfunction-associated steatohepatitis(MASH),are driven by chronic overnutrition,multiple genetic susceptibility factors,and pathogenic consequences,including hepatocyte damage and liver inflammation.Hepatic inflammation is the key event fueling the conversion from simple steatosis to steatohepatitis and fibrosis.Current therapies for MASH,including the recently approved thyroid hormone receptor-beta agonist resmetirom or the available incretin mimetics,mainly target metabolic injury to the liver but not inflammation directly.In this review,we provide an in-depth discussion of current data related to the immunological mechanisms of MASLD and summarize the effects of current and experimental therapies on immunoregulation in MASLD.
基金supported by the National Natural Science Foundation of China(No.82170609)NSFC-RGC Forum for Young Scholars(No.82411560273)+1 种基金Nanjing Drum Tower Hospital Academic Innovation Peak Project(No.2024-DF-03)the Natural Science Foundation of Jiangsu Province(No.BK20231118).
文摘Aims:The synergistic impact of alcohol consumption and cardiometabolic risk factors(CMRFs)on liver health remains unclear.Herein,we aimed to investigate the interplay between varying levels of alcohol consumption and the number of CMRFs on all-cause mortality in individuals with metabolic dysfunction-associated steatotic liver disease(MASLD)and metabolic and alcohol-associated liver disease(MetALD).Methods:Adult participants with ultrasound-proven hepatic steatosis were identified using the Third National Health and Nutrition Examination Survey(NHANES III)database.Multivariate Cox regression was applied to investigate the association between incremental alcohol consumption and the number of CMRFs,with all-cause mortality as the outcome.The E-value was calculated to assess the robustness of the associations,and additive interaction models were used to explore the synergistic effects of alcohol consumption and CMRFs on mortality.Results:A total of 2161 individuals(1957 with MASLD and 204 with MetALD)between the Years 1988 and 1994 were included in the analysis.During a follow-up period of 51,719 person-years,the overall mortality rate was 1.46%per person-year.Stratification by age showed an increased mortality risk associated with CMRFs and alcohol consumption in individuals aged<65 years,especially among those with 3-5 CMRFs(hazard ratio:3.15-5.71,all p<0.05).Additive interaction models also supported a synergistic effect in this subgroup,while no such trend was observed in those aged≥65 years.Conclusion:Among individuals with MASLD/MetALD and MASLD alone,a significant synergistic effect between alcohol consumption and CMRFs on mortality risk was found in those aged<65 years.This suggests an age-stratified approach for managing modifiable risk factors in individuals with MASLD or MetALD.
基金supported by the National Natural Science Foundation of China(Grant Nos.U21A20420,82373895 and 82304517)the Zhejiang Provincial Natural Science Foundation(Grant No.LQ23H310009,China).
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD),the most prevalent chronic liver condition globally,lacks adequate and effective therapeutic remedies in clinical practice.Recent studies have increasingly highlighted the close connection between the ubiquitin–proteasome system(UPS)and the progression of MASLD.This relationship is crucial for understanding the disease's underlying mechanism.As a sophisticated process,the UPS govern protein stability and function,maintaining protein homeostasis,thus influencing a multitude of elements and biological events of eukaryotic cells.It comprises four enzyme families,namely,ubiquitin-activating enzymes(E1),ubiquitin-conjugating enzymes(E2),ubiquitin-protein ligases(E3),and deubiquitinating enzymes(DUBs).This review aims to delve into the array of pathways and therapeutic targets implicated in the ubiquitination within the pathogenesis of MASLD.Therefore,this review unveils the role of ubiquitination in MASLD while spotlighting potential therapeutic targets within the context of this disease.
基金supported by a Digital Clinician Scientist fellowship from the Berlin Institute of Health.Work in the lab of FT has been funded by the German Research Foundation(DFG Ta434/8-1 and CRC1382,Project-ID 403224013).
文摘The new European clinical practice guidelines from three scientific societies(European Association for the Study of the Liver,European Association for the Study of Diabetes and European Association for the Study of Obesity)on the management of metabolic dysfunction-associated steatotic liver disease(MASLD)provide detailed recommendations on diagnosis,risk stratification,monitoring strategies,treatment and prevention.Lifestyle interventions(eg,weight reduction,Mediterranean diet,exercise,alcohol abstinence)and the treatment of cardiometabolic risk factors continue to be the mainstay of treatment and prevention of the disease.Incretin mimetics that are approved to treat obesity and/or type 2 diabetes such as semaglutide and tirzepatide have benefits for ameliorating metabolic dysfunction-associated steatohepatitis(MASH).Novel developments include adapted strategies for screening(case finding)using non-invasive tests(NITs)with a focus on detecting fibrosis or cirrhosis,risk-adjusted monitoring of MASLD by NITs as well as the recommendation to use,if locally approved,the thyroid hormone receptorβ-agonist resmetirom in patients with non-cirrhotic MASH fibrosis(≥F2 stage).
基金funded by national funds through FCT-Portuguese Foundation for Science and Technology,under the scope of the Cardiovascular R&D Center-UnIC(UIDB/00051/2020 and UIDP/00051/2020)JC-L was supported by a travel grant fellowship from the Research Foundation Flanders(V465523N)SV-S is a principal investigator in the BMFTR Cluster4Future CurATime(CurATime project microbAIome,03ZU1202CB)funded by the Federal Ministry of Research,Technology and Space(BMFTR).
文摘Background Metabolic dysfunction-associated steatotic liver disease(MASLD)is the leading cause of chronic liver disease globally,with rising prevalence linked to metabolic syndrome(MetS).Excessive liver fat accumulation(steatosis)worsens disease progression and MASLD prognosis.Moreover,gut microbiota dysbiosis might promote steatosis,accelerating the disease progression to severe stages.Identifying gut microbiota signatures specific to steatosis severity might improve its diagnosis and inform personalised interventions in MASLD.This study aimed to characterise associations between gut microbiota composition and hepatic steatosis severity in a cohort of patients with MASLD/MetS.Ultimately,we aimed to assess the potential for microbiota features to enhance the diagnosis of severe steatosis.Methods A cross-sectional cohort of 61 patients with MetS with extensive clinical history was recruited at different stages of MASLD.Transient elastography was used to evaluate liver fibrosis and steatosis severity.Participants’faecal microbiota were profiled using 16S rRNA gene sequencing.Statistical analyses first identified correlations between microbiota profiles and patients’phenotypes,while disentangling important confounders such as medication.Identified features were then used to build predictive models for diagnosing severe steatosis.Results High steatosis severity was distinctly associated with a higher prevalence of the inflammation-associated Bacteroides 2(Bact2)-enterotype,accompanied by a lower proportion of beneficial commensals(eg,Akkermansia)and a higher proportion of opportunistic bacteria(eg,Streptococcus).Patients harbouring a Bact2-enterotype reached severe steatosis at lower Fatty Liver Index(FLI)thresholds.Using Bact2-carrier status together with FLI in a predictive model significantly improved the classification of severe steatosis(accuracy 90%,receiver operating characteristics 96%)when compared with FLI alone.Conclusion Gut microbiota composition and dysbiosis(defined as Bact2-enterotype)are distinctly associated with steatosis severity in MASLD/MetS.Patient stratification by microbiota composition enhances the diagnostic classification of severe steatosis in MASLD,suggesting a potential for personalised interventions in patients with microbiota dysbiosis.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is a global health burden that requires early screening,diagnosis,and intervention MASLD is a leading cause of chronic liver disease globally,with an estimated prevalence of 38%worldwide(1,2).MASLD is the new term that replaces what was previously known as non-alcoholic fatty liver disease(NAFLD).
基金supported by Japan Agency for Medical Research and Development(JP25fk0210123 to M.K.)Japanese Ministry of Health,Labour and Welfare(23HC2001 to M.K.)+1 种基金from Japan Agency for Medical Research and Development(JP25fk0310535,JP25fk0210174,and JP25fk0210123 to N.T.)Japanese Ministry of Health,Labour and Welfare(23HC2003 and 23HC2002 to N.T.).
文摘The prevalence of cirrhosis and hepatocellular carcinoma resulting from metabolic dysfunction-associated steatotic liver disease(MASLD)is increasing,posing a significant burden on both the economy and public health(1,2).Although the need for effective therapeutic strategies for MASLD is growing,pharmacologic options remain limited,with resmetirom currently the only approved drug.Consequently,lifestyle modification-particularly weight reduction through diet and exercise-remains the cornerstone of MASLD management.
基金supported by research grants from the National Natural Science Foundation of China(82471593 to Junxia Min,and 32330047 and 31930057 to Fudi Wang)。
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)remains a rapidly growing global health burden.Here,we report that the nonessential amino acid(NEAA)transporter SLC7A11 plays a key role in MASLD.In patients with MASLD,we found high expression levels of SLC7A11 that were correlated directly with clinical grade.Using both loss-of-function and gain-of-function genetic models,we found that Slc7a11 deficiency accelerated MASLD progression via classic cystine/cysteine deficiencyinduced ferroptosis,while serine deficiency and a resulting impairment in de novo cysteine production were attributed to ferroptosis-induced MASLD progression in mice overexpressing hepatic Slc7a11.Consistent with these findings,we found that both serine supplementation and blocking ferroptosis significantly alleviated MASLD,and the serum serine/glutamate ratio was significantly lower in these preclinical disease models,suggesting that it might serve as a prognostic biomarker for MASLD in patients.These findings indicate that defects in NEAA metabolism are involved in the progression of MASLD and that serine deficiency-triggered ferroptosis may provide a therapeutic target for its treatment.
文摘In the present narrative review,we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease(NAFLD)/metabolic dysfunction-associated steatotic liver disease(MASLD).We start by reviewing the epidemiology of the condition and its close association with obesity and type 2 diabetes.We then discuss how randomized-controlled trials are performed following guidance from regulatory agencies,including differences and similarities between requirements of the US Food and Drug Administration and the European Medicine Agency.Difficulties and hurdles related to limitations of liver biopsy,a large number of screening failures in recruiting patients,as well as unpredictable response rates in the placebo group are evaluated.Finally,we recapitulate the strategies employed for potential drug treatments of this orphan condition.The first is to repurpose drugs that originally targeted T2DM and/or obesity,such as pioglitazone,glucagon-like peptide 1 receptor agonists(liraglutide and semaglutide),multi-agonists(tirzepatide and retatrutide),and sodium-glucose transporter 2 inhibitors.The second is to develop drugs specifically targeting NAFLD/MASLD.Among those,we focused on resmetirom,fibroblast growth factor 21 analogs,and lanifibranor,as they are currently in Phase 3 of their clinical trial development.While many failures have characterized the field of pharmacological treatment of NAFLD/MASLD in the past,it is likely that approval of the first treatments is near.As occurs in many chronic conditions,combination therapy might lead to better outcomes.In the case of non-alcoholic steatohepatitis,we speculate that drugs treating underlying metabolic co-morbidities might play a bigger role in the earlier stages of disease,while liver-targeting molecules will become vital in patients with more advanced disease in terms of inflammation and fibrosis.
基金supported by the National Key Research and Development Program of China(2022YFA0806503)the National Natural Science Foundation of China(81972625 and 32201217)+3 种基金Liaoning Revitalization Talents Program(XLYC2002035)Liaoning Science and Technology Innovation Funding(20230101-JH2/1013)the Innovation Program of Science and Research from Dalian Institute of Chemical Physics,Chinese Academy of Sciences(DICP I202129 and DICP I202209)the Science and Technology Innovation Fund(Youth Science and Technology Star)of Dalian(2021RQ009 and 2023RQ040).
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis(MASH),cirrhosis,and cancer.The zonal distribution of biomolecules in the liver is implicated in mediat-ing the disease progression.Recently,G-protein-coupled receptor 35(GPR35)has been highlighted to play a role in MASLD,but the precise mechanism is not fully understood,particularly,in a liver-zonal manner.Here,we aimed to identify spatially distributed specific genes and metabolites in different liver zonation that are regulated by GPR35 in MASLD,by combining lipid metabolomics,spatial transcriptomics(ST),and spatial metabolomics(SM).We found that GPR35 influenced lipid accumulation,inflammatory and metabolism-related factors in specific regions,notably affecting the anti-inflammation factor ELF4(E74 like E-twenty six(ETS)tran-scription factor 4),lipid homeostasis key factor CIDEA(cell death-inducing DNA fragmentation factor alpha(DFFA)-like effector A),and the injury response-related genes SAA1/2/3(serum amyloid A1/2/3),thereby impacting MASLD progression.Furthermore,SM elucidated specific metabolite distributions across different liver regions,such as C10H11N4O7P(3ʹ,5ʹ-cyclic inosine monophosphate(3ʹ,5ʹ-IMP))for the central vein,and this metabolite significantly decreased in the liver zones of GPR35-deficient mice during MASLD progression.Taken together,GPR35 regulates hepatocyte damage repair,controls inflammation,and prevents MASLD progression by influencing phospholipid homeostasis and gene expression in a zonal manner.
文摘My invited commentary discusses a recent paper published by Ebrahimi et al.[28].To this end,the definitions of nonalcoholic fatty liver disease(NAFLD),metabolic dysfunction-associated fatty liver disease(MAFLD),and the most recently proposed metabolic dysfunction-associated steatotic liver disease(MASLD)are reviewed.For brevity,the overarching definition of metabolic fatty liver syndromes(MFLS)is utilized to allude to NAFLD/MAFLD/MASLD collectively,although each nomenclature identifies different diagnostic criteria and distinct patient populations.Ebrahimi and colleagues conducted an analysis using data from the National Swedish Multigeneration archive,involving 38,018 MASLD first-degree relatives(FDRs)and 9,381 MASLD spouses,alongside 197,303 comparator FDRs and 47,572 comparator spouses.These authors followed these groups for a median of 17.6 years and reported a definite familial aggregation of adverse liver-related events among families of MASLD individuals.These events comprise increased relative risks of hepatocellular carcinoma(HCC),major chronic liver disease,and mortality owing to hepatic causes.I comment on this study with reference to the ongoing changes in terminology describing MFLS and to sexual dimorphism exhibited by MFLS.It is concluded that the study by Ebrahimi adds another piece to the puzzle of knowledge requested to implement those precision medicine approaches that are eagerly awaited in the field of MFLS.
基金supported by“Scientific and Technological Research Council of Turkey(TUBITAK)”with the grant number 119S698.
文摘Aim:Hepatocellular carcinoma(HCC)in patients with Metabolic dysfunction-associated steatotic liver disease(MASLD,formerly NAFLD)is expected to be a significant public health issue in the near future.Therefore,understanding the tumor microenvironment interactions in MASLD-induced HCC is crucial,and the development of relevant preclinical models is needed.Hence,we aimed to determine the effects of a MASLD-mimicking microenvironment(ME)on the aggressiveness of HCC cells and identify target genes that drive HCC by developing a 3D-in vitro co-culture system.Methods:A 3D co-culture system mimicking the MASLD-ME was created with LX-2 liver stellate cells embedded in 3D collagen gel in the lower and SNU-449 HCC cells on the upper parts of Boyden chambers,and cells were grown in an optimized metabolic medium(MM).The effects of MASLD-ME on motility,sphere formation,proliferation,and cell cycle of SNU-449 cells were tested by Boyden chamber,3D sphere formation,XTT,and Flow cytometry,respectively.The protein expression/activation profiles of motile SNU-449 cells that passed the membrane toward MASLD-ME or control condition were investigated using a multiplex protein profiling system DigiWest and confirmed with RT-PCR,WB,and Flow cytometry.IDH2 levels were examined in primary human HCC and adjacent liver tissues by IHC and in TCGA and CPTAC cohorts by bioinformatics tools.Results:MM treatment increased fat accumulation,motility,and spheroid formation of both SNU-449 and LX-2 cells.MASLD-ME induced activation of LX2 cells,leading to the formation of bigger colonies with many intrusions compared to related controls.DigiWest analysis showed that metabolism-related proteins such as IDH2 were the most affected molecules in SNU-449 cells that migrated toward the MASLD-ME compared to those that migrated toward the control condition.Downregulation of IDH2 expression was confirmed in SNU-449 cells grown in MASLD-ME,in primary HCC tumor samples by IHC,and in HCC patient cohorts by bioinformatics analysis.Conclusion:This study reports the potential involvement of MASLD-ME in the downregulation of IDH2 expression and promoted motility and colonization capacity of HCC cells.The 3D MASLD model presented in this study may be useful in investigating the mechanistic roles of MASLD-ME in HCC.
文摘目的探究血浆致动脉粥样硬化指数(atherogenic index of plasma,AIP)与代谢功能障碍相关脂肪性肝病(metabolism-associated steatotic liver disease,MASLD)的关系,评估AIP作为MASLD风险预测指标的潜在价值,为早期预防和临床干预提供参考。方法纳入2021年6月至2023年5月西安交通大学第二附属医院4850名健康体检者。按AIP四分位数将全体受试者由低到高分为4组(Q1~Q4),比较各组间生化指标与MASLD患病率。采用Logistic回归、亚组分析、限制性立方样条(restricted cubic splines,RCS)等方法探究AIP与MASLD之间的相关性。结果共纳入4850例受试者,MASLD患病率为26.08%(1265例)。Q1~Q4组MASLD的患病率分别为4.0%、13.8%、30.8%、55.6%,患病率随AIP四分位数组级升高而呈显著递增趋势(P<0.001)。与Q1组相比,Q2~Q4组男性占比、身体质量指数(body mass index,BMI)、吸烟者占比、超重肥胖占比、腹型肥胖占比、糖尿病前期占比、高血压占比、血尿酸及脂肪肝指数(fatty liver index,FLI)水平均明显增加,差异有统计学意义(P<0.001)。随着AIP的增加,血清总胆固醇、三酰甘油、低密度脂蛋白胆固醇水平显著增加,高密度脂蛋白胆固醇水平则显著降低(P<0.001)。RCS曲线显示随着AIP增加,MASLD的患病风险显著增加,AIP与MASLD患病风险之间呈线性关系。Logistic回归显示,在调整混杂因素后,Q4组中MASLD发生风险为Q1组的8.71倍(OR=8.71,95%CI:6.20~12.23,P<0.001)。建立的复合模型具有更高的判别性能(AUC=0.883,95%CI:0.873~0.892)。交互作用分析提示AIP与BMI、高血压及糖尿病前期存在显著交互作用(P<0.05),在无上述代谢异常的人群中,AIP与MASLD的关联更为显著。结论AIP升高与MASLD发病风险增加显著相关,尤其在BMI正常组、血压正常组及血糖正常组中关联更强,提示AIP有望作为MASLD早期筛查的潜在指标。
