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),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
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
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
Metabolic dysfunction-associated steatotic liver disease(MASLD)has a high global incidence and associated with increased lipid accumulation in hepatocytes,elevated hepatic enzyme levels,liver fibrosis,and hepatic carc...Metabolic dysfunction-associated steatotic liver disease(MASLD)has a high global incidence and associated with increased lipid accumulation in hepatocytes,elevated hepatic enzyme levels,liver fibrosis,and hepatic carcinoma.Despite decades of research and significant advancements,the treatment of MASLD still faces formidable challenges.Nanoprobes for diagnostics and nanomedicine for targeted drug delivery to the liver present promising options for MASLD diagnosis and treatment,enhancing both imaging contrast and bioavailability.Here,we review recent advances in nanotechnology applied to MASLD diagnosis and treatment,specifically focusing on drug delivery systems targeting hepatocytes,hepatic stellate cells,Kupffer cells,and liver sinusoidal endothelial cells.This review aims to provide an overview of nanomedicine’s potential in early MASLD diagnosis and therapeutic interventions,addressing related complications.展开更多
With the prevalence of obesity,metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide and can cause a series of serious complications.The pathogenesis...With the prevalence of obesity,metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide and can cause a series of serious complications.The pathogenesis of MASLD is complex,characterized by oxidative stress,impaired mitochondrial function and lipid metabolism,and cellular inflammation.Mitochondrial biology and function are central to the physiology of the liver.It has been suggested that mitochondrial oxidative stress plays a crucial role in MASLD progression.Excessive oxidative stress response is an important trigger for the occurrence and development of MASLD.In this review,we aim to focus on the recent advances in understanding mitochondrial oxidative stress-related mechanisms in the progression of MASLD.The in-depth elaboration of its related mechanisms is hoped to help find effective methods for treating MASLD.展开更多
Background:Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease(MASLD).We aimed to investig...Background:Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease(MASLD).We aimed to investigate the causative role and molecular mechanisms of P.copri in pediatric MASLD.Methods:C57BL/6 J mice aged 3 weeks were fed a high-fat diet(HFD)and orally administered with P.copri for 5 weeks.We assessed the key features of MASLD and the gut microbiota profile.By untargeted metabolomics on mouse fecal samples and the supernatant from P.copri culture,we identified P.copriderived metabolite and tested its effects in vitro.Results:In HFD-fed mice,administration of P.copri significantly promoted liver steatosis.Genes associated with inflammation and fibrosis were significantly upregulated in the livers from the HFD+P.copri group compared with those in the livers from the HFD group.In addition,P.copri reduced gut microbial diversity,increased the proportion of Firmicutes and decreased Bacteroidota.Importantly,5-aminopentanoic acid(5-AVA)was significantly enriched in both mouse feces from the HFD+P.copri group and the culture supernatant of P.copri.In vitro,5-AVA aggravated palmitic acid-induced lipid accumulation in HepG2 cells and primary mouse hepatocytes.Mechanistically,P.copri-produced 5-AVA exacerbated hepatic steatosis by promoting lipogenesis and fatty acid uptake,while also reducing hepatic very-low-density lipoprotein export.Conclusions:Our findings demonstrated that P.copri promotes liver steatosis in HFD-fed juvenile mice through its metabolite 5-AVA,suggesting its potential as a therapeutic target for the management of pediatric MASLD.展开更多
Liver fibrosis is an important predictor of mortality.Liver disease case definitions changed in 2023.These definitions include an easily over-looked group with no traditional etiology(NTE)of liver disease and no steat...Liver fibrosis is an important predictor of mortality.Liver disease case definitions changed in 2023.These definitions include an easily over-looked group with no traditional etiology(NTE)of liver disease and no steatosis.We analyzed heavy metals and cardiometabolic risk factors(CMRFs)as fibrosis risk factors in the NTE group and in people with another newly-defined condition,metabolic dysfunction-associated steatotic liver disease(MASLD).Two National Health and Nutrition Examination Survey(NHANES)datasets were analyzed.In NHANES Ⅲ(1988–1994),fibrosis and steatosis were defined by Fibrosis-4 scores and ultrasound,respectively,in 12,208 adults.In NHANES 2017–2020,fibrosis and steatosis were defined by transient elastography and the controlled attenuation parameter(CAP)in 5525 adults.Fibrosis risk factors varied over time and by race/ethnicity.In the earlier dataset,NTE-fibrosis had a positive,non-significant,association with high blood levels of lead(Pb).MASLD-fibrosis was associated with Pb(OR=2.5,95%CI,1.4–4.4)and not with CMRFs in non-Hispanic Blacks but was associated with CMRFs in non-Hispanic Whites.Heavy metal exposures fell between the two time periods.In the later dataset,NTE-fibrosis was associated with Pb(OR=4.2,95%CI,2.6–6.8)and cadmium(OR=1.8,95%CI,1.1–3.0)in the total population,but not with most CMRFs.MASLD-fibrosis was strongly-significantly associated with CMRFs in every racial/ethnic group except non-Hispanic Blacks in whom CMRFs were only weakly associated with MASLD-fibrosis.Heavy metal pollution,which disproportionately impacts minoritized populations,decreased over time,but remained strongly associated with liver fibrosis in people lacking traditional etiological factors for liver disease.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
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.
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.
基金supported in part by Noncommunicable Chronic Diseases-National Science and Technology Major Project(2023ZD0508800)National Natural Science Foundation of China(32401171)+4 种基金the Key Research and Development Program of Jiangsu Province(BE2023767a)Fundamental Research Fund of Southeast University(3290002406A2)Research Personnel Cultivation Programme of Zhongda Hospital,Southeast University(CZXM-GSP-RC125)Distinguished Medical Specialists in Jiangsu Province(CZXM-RC-43)Changjiang Scholars Talent Cultivation Project of Zhongda Hospital of Southeast University(2023YJXYYRCPY03).
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)has a high global incidence and associated with increased lipid accumulation in hepatocytes,elevated hepatic enzyme levels,liver fibrosis,and hepatic carcinoma.Despite decades of research and significant advancements,the treatment of MASLD still faces formidable challenges.Nanoprobes for diagnostics and nanomedicine for targeted drug delivery to the liver present promising options for MASLD diagnosis and treatment,enhancing both imaging contrast and bioavailability.Here,we review recent advances in nanotechnology applied to MASLD diagnosis and treatment,specifically focusing on drug delivery systems targeting hepatocytes,hepatic stellate cells,Kupffer cells,and liver sinusoidal endothelial cells.This review aims to provide an overview of nanomedicine’s potential in early MASLD diagnosis and therapeutic interventions,addressing related complications.
基金supported by grants from the Top Medical Expert Team of Wuxi Taihu Talent Plan(Grant Nos.DJTD202106,GDTD202105 and YXTD202101)Medical Key Discipline Program of Wuxi Health Commission(Grant Nos.ZDXK2021007 and CXTD2021005)+1 种基金Top Talent Support Program for Young and MiddleAged People of Wuxi Health Committee(Grant No.BJ2023090)Scientific Research Program of Wuxi Health Commission(Grant Nos.Z20210 and M202208).
文摘With the prevalence of obesity,metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide and can cause a series of serious complications.The pathogenesis of MASLD is complex,characterized by oxidative stress,impaired mitochondrial function and lipid metabolism,and cellular inflammation.Mitochondrial biology and function are central to the physiology of the liver.It has been suggested that mitochondrial oxidative stress plays a crucial role in MASLD progression.Excessive oxidative stress response is an important trigger for the occurrence and development of MASLD.In this review,we aim to focus on the recent advances in understanding mitochondrial oxidative stress-related mechanisms in the progression of MASLD.The in-depth elaboration of its related mechanisms is hoped to help find effective methods for treating MASLD.
基金supported by grants from the National Key R&D Program of China(2022YFA1305600)National Natural Science Foundation of China(82100950,82470602,and 82470600)Natural Science Foundation of Shanghai(23ZR1452600)。
文摘Background:Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease(MASLD).We aimed to investigate the causative role and molecular mechanisms of P.copri in pediatric MASLD.Methods:C57BL/6 J mice aged 3 weeks were fed a high-fat diet(HFD)and orally administered with P.copri for 5 weeks.We assessed the key features of MASLD and the gut microbiota profile.By untargeted metabolomics on mouse fecal samples and the supernatant from P.copri culture,we identified P.copriderived metabolite and tested its effects in vitro.Results:In HFD-fed mice,administration of P.copri significantly promoted liver steatosis.Genes associated with inflammation and fibrosis were significantly upregulated in the livers from the HFD+P.copri group compared with those in the livers from the HFD group.In addition,P.copri reduced gut microbial diversity,increased the proportion of Firmicutes and decreased Bacteroidota.Importantly,5-aminopentanoic acid(5-AVA)was significantly enriched in both mouse feces from the HFD+P.copri group and the culture supernatant of P.copri.In vitro,5-AVA aggravated palmitic acid-induced lipid accumulation in HepG2 cells and primary mouse hepatocytes.Mechanistically,P.copri-produced 5-AVA exacerbated hepatic steatosis by promoting lipogenesis and fatty acid uptake,while also reducing hepatic very-low-density lipoprotein export.Conclusions:Our findings demonstrated that P.copri promotes liver steatosis in HFD-fed juvenile mice through its metabolite 5-AVA,suggesting its potential as a therapeutic target for the management of pediatric MASLD.
基金supported by the Prevent Cancer Foundation(No.PCF 604934)the National Institute for Occupational Safety and Health(Nos.U01OH011489,U01OH012263,and U01 OH012622)Pfizer 70472597.
文摘Liver fibrosis is an important predictor of mortality.Liver disease case definitions changed in 2023.These definitions include an easily over-looked group with no traditional etiology(NTE)of liver disease and no steatosis.We analyzed heavy metals and cardiometabolic risk factors(CMRFs)as fibrosis risk factors in the NTE group and in people with another newly-defined condition,metabolic dysfunction-associated steatotic liver disease(MASLD).Two National Health and Nutrition Examination Survey(NHANES)datasets were analyzed.In NHANES Ⅲ(1988–1994),fibrosis and steatosis were defined by Fibrosis-4 scores and ultrasound,respectively,in 12,208 adults.In NHANES 2017–2020,fibrosis and steatosis were defined by transient elastography and the controlled attenuation parameter(CAP)in 5525 adults.Fibrosis risk factors varied over time and by race/ethnicity.In the earlier dataset,NTE-fibrosis had a positive,non-significant,association with high blood levels of lead(Pb).MASLD-fibrosis was associated with Pb(OR=2.5,95%CI,1.4–4.4)and not with CMRFs in non-Hispanic Blacks but was associated with CMRFs in non-Hispanic Whites.Heavy metal exposures fell between the two time periods.In the later dataset,NTE-fibrosis was associated with Pb(OR=4.2,95%CI,2.6–6.8)and cadmium(OR=1.8,95%CI,1.1–3.0)in the total population,but not with most CMRFs.MASLD-fibrosis was strongly-significantly associated with CMRFs in every racial/ethnic group except non-Hispanic Blacks in whom CMRFs were only weakly associated with MASLD-fibrosis.Heavy metal pollution,which disproportionately impacts minoritized populations,decreased over time,but remained strongly associated with liver fibrosis in people lacking traditional etiological factors for liver disease.
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.
