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
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
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
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
Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most prevalent chronic liver disease globally,with only one Food and Drug Administration(FDA)-approved drug for its treatment.Given MASLD's com...Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most prevalent chronic liver disease globally,with only one Food and Drug Administration(FDA)-approved drug for its treatment.Given MASLD's complex pathophysiology,ther-apies that simultaneously target multiple pathways are highly desirable.One promising approach is dual-modulation of the famesoid X receptor(FXR),which regulates lipid and bile acid metabolism.However,FXR agonists alone are insufficient due to their limited anti-inflammatory effects.This study aimed to dto identify natural products capable of both FXR activation and inflammation inhibition to provide a comprehensive therapeutic approach for MASLD.Potential FXR ligands from the Natural Product Library were predicted via virtual screening using the Protein Preparation Wizard module in Schrodinger(2018)for molecular docking.Direct binding and regulation of candidate compounds on FXR were analyzed using surface plasmon resonance(SPR)binding assay,reporter gene ana-lysis,and reverse transcription-polymerase chain reaction(RT-PCR).The anti-inflammatory properties of these compounds were eval-uated in AML12 cells treated with tumor necrosis factor-alpha(TNF-α).Dual-function compounds with FXR agonism and inflamma-tion inhibition were further identified in cells transfected with Fxr siRNA and treated with TNF-α.The effects of these dual-function compounds on lipid accumulation and inflammation were evaluated in cells treated with palmitic acid.Results revealed that 17 natural products were predicted via computational molecular docking as potential FXR agonists,with 15 exhibiting a strong affinity for FXR recombinant protein.Nine isoflavone compounds significantly enhanced FXR reporter luciferase activity and the mRNA expressions of Shp and Ostb.Structure-activity relationship analysis indicated that introducing isopropyl or methoxy groups at the C7 position or a methoxy group at the C6 position could enhance the agonistic efficacy of isoflavones.Three compounds(2,6,and 8)were identified as dual-function natural products functioning as FXR agonists and inflammatory inhibitors,while one compound(12)acted as an FXR agonist to inhibit inflammation.These natural products protected hepatocytes against palmitic acid-induced lipid accumulation and in-flammation.In conclusion,compounds 2,6,and 8(genistein,biochanin A,and 7-methoxyisoflavone,respectively)were identified as dual-function bioactive products that transactivate FXR and inhibit inflammation,serving as potential candidates or lead compounds for MASLD therapy.展开更多
Given the global prevalence and rising incidence of metabolic dysfunction-associated steatotic liver disease(MASLD),the absence of licensed medications is striking.A deeper understanding of the heterogeneous nature of...Given the global prevalence and rising incidence of metabolic dysfunction-associated steatotic liver disease(MASLD),the absence of licensed medications is striking.A deeper understanding of the heterogeneous nature of MASLD has recently contributed to the discovery of novel groups of agents and the potential repurposing of currently available medications.MASLD therapies center on four major pathways.Considering the close relationship between MASLD and type 2 diabetes,the first approach involves antidiabetic medications,including incretins,thiazolidinedione insulin sensitizers,and sodium-glucose cotransporter 2 inhibitors.The second approach targets hepatic lipid accumulation and the resultant metabolic stress.Agents in this group include peroxisome proliferatoractivated receptor agonists(e.g.,pioglitazone,elafibranor,saroglitazar),bile acid-farnesoid X receptor axis regulators(obeticholic acid),de novo lipogenesis inhibitors(aramchol,NDI-010976),and fibroblast growth factor 21/19 analogs.The third approach focuses on targeting oxidative stress,inflammation,and fibrosis.Agents in this group include antioxi-dants(vitamin E),tumor necrosis factor a pathway regulators(emricasan,pentoxifylline,ZSP1601),and immune modulators(cenicriviroc,belapectin).The final group targets the gut(IMM-124e,solithromycin).Combination therapies targeting different pathogenetic pathways may provide an alternative to MASLD treatment with higher efficacy and fewer side effects.This review aimed to provide an update on these medications.展开更多
Sarcopenia is a well-known complication of chronic liver disease(CLD),and it is almost always observed in patients with cirrhosis,at least in those with decompensated disease.Since nonalcoholic fatty liver disease(NAF...Sarcopenia is a well-known complication of chronic liver disease(CLD),and it is almost always observed in patients with cirrhosis,at least in those with decompensated disease.Since nonalcoholic fatty liver disease(NAFLD),recently renamed metabolic dysfunction-associated steatotic liver disease(MASLD),is becoming the leading cause of end-stage liver disease,a new scenario characterized by the frequent coexistence of NAFLD,obesity,and sarcopenia is emerging.Although it is not yet resolved whether the bidirectional relationship between sarcopenia and NAFLD subtends causal determinants,it is clear that the interaction of these two conditions is associated with an increased risk of poor outcomes.Notably,during the course of CLD,deregulation of the liver-muscle-adipose tissue axis has been described.Unfortunately,owing to the lack of properly designed studies,specific therapeutic guidelines for patients with sarcopenia in the context of NAFLD-related CLD have not yet been defined.Strategies aimed to induce the loss of fat mass together with the maintenance of lean body mass seem most appropriate.This can be achieved by properly designed diets integrated with specific nutritional supplementations and accompanied by adequate physical exercise.Future studies aiming to add to the knowledge of the correct assessment and approach to sarcopenia in the context of NAFLD-related CLD are eagerly awaited.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD),formerly known as non-alcoholic fatty liver disease,has a high global prevalence and can progress to metabolic dysfunction-associated steatohepatitis,cir...Metabolic dysfunction-associated steatotic liver disease(MASLD),formerly known as non-alcoholic fatty liver disease,has a high global prevalence and can progress to metabolic dysfunction-associated steatohepatitis,cirrhosis,and hepatocellular carcinoma.The pathogenesis of MASLD is primarily driven by disturbances in hepatic lipid metabolism,involving six key processes:increased hepatic fatty acid uptake,enhanced fatty acid synthesis,reduced oxidative degradation of fatty acids,increased cholesterol uptake,elevated cholesterol synthesis,and increased bile acid synthesis.Consequently,maintaining hepatic lipid metabolic homeostasis is essential for effective MASLD management.Numerous novel molecules and Chinese proprietary medicines have demonstrated promising therapeutic potential in treating MASLD,primarily by inhibiting lipid synthesis and promoting lipid oxidation.In this review,we summarized recent research on MASLD,elucidated the molecular mechanisms by which lipid metabolism disorders contribute to MASLD pathogenesis,and discussed various lipid metabolism-targeted therapeutic approaches for MASLD.展开更多
The onset of metabolic dysfunction-associated steatohepatitis(MASH)or non-alcoholic steatohepatitis(NASH)represents a tipping point leading to liver injury and subsequent hepatic complications in the natural progressi...The onset of metabolic dysfunction-associated steatohepatitis(MASH)or non-alcoholic steatohepatitis(NASH)represents a tipping point leading to liver injury and subsequent hepatic complications in the natural progression of what is now termed metabolic dysfunction-associated steatotic liver diseases(MASLD),formerly known as non-alcoholic fatty liver disease(NAFLD).With no pharmacological treat-ment currently available for MASH/NASH,the race is on to develop drugs targeting multiple facets of hepatic metabolism,inflammation,and pro-fibrotic events,which are major drivers of MASH.Nuclear receptors(NRs)regulate genomic transcription upon binding to lipophilic ligands and govern multiple aspects of liver metabolism and inflammation.Ligands of NRs may include hormones,lipids,bile acids,and synthetic ligands,which upon binding to NRs regulate the transcriptional activities of target genes.NR ligands are presently the most promising drug candidates expected to receive approval from the United States Food and Drug Administration as a pharmacological treatment for MASH.This review aims to cover the current understanding of NRs,including nuclear hormone receptors,non-steroid hormone receptors,circadian NRs,and orphan NRs,which are currently undergoing clinical trials for MASH treatment,along with NRs that have shown promising results in preclinical studies.展开更多
Metabolic-dysfunction associated steatotic liver disease(MASLD),formerly known as non-alcoholic fatty liver disease(NAFLD)(1),is characterized by the accumulation of fat in the liver cells,independent of excessive alc...Metabolic-dysfunction associated steatotic liver disease(MASLD),formerly known as non-alcoholic fatty liver disease(NAFLD)(1),is characterized by the accumulation of fat in the liver cells,independent of excessive alcohol consumption and has emerged as the most prevalent chronic liver condition in Western countries,underscoring a significant public health concern(2).The progression of MASLD to advanced fibrosis,marked by excessive extracellular matrix deposition and scar tissue formation,is a critical stage in MASLD natural history that significantly increases the risk of liver-related complications mortality(3).Non-invasive tests(NITs),such as liver stiffness measurement(LSM)with transient elastography(TE)and serum biomarkers,have gained prominence for assessing liver fibrosis in patients with suspected/confirmed NAFLD,offering a safer and less invasive alternative to liver biopsy(4).展开更多
We read with great interest the informative study by Armandi et al.,which shed light on the potential role of serum ferritin in predicting the long-term prognosis of patients with metabolic dysfunction-associated stea...We read with great interest the informative study by Armandi et al.,which shed light on the potential role of serum ferritin in predicting the long-term prognosis of patients with metabolic dysfunction-associated steatotic liver disease(1).However,there remain certain facets requiring in-depth investigation and interpretation.First of all,the study found that integrating stepwise increased ferritin thresholds(215.5 and 272µg/L)into predictive models can improve the performance of fibrosis-4(FIB-4)and Non-Alcoholic Fatty Liver Disease Fibrosis Score(NFS)in the longitudinal risk assessment of liver-related events and overall mortality.However,it has been suggested that metabolic hyperferritinaemia(MHF)appears to exhibit a male predominance(2,3).Since the study primarily comprised male participants(65%),it raises the query of whether the ferritin threshold based on the entire population can accurately predict risks within female patients.Therefore,a sex-specific analysis is warranted to ensure a more precise evaluation.展开更多
Liver disease associated with metabolic dysfunction now affects more than 30%of the world’s population(1).Historically known as non-alcoholic fatty liver disease(NAFLD)is caused by obesity,lack of exercise,and a west...Liver disease associated with metabolic dysfunction now affects more than 30%of the world’s population(1).Historically known as non-alcoholic fatty liver disease(NAFLD)is caused by obesity,lack of exercise,and a westernised lifestyle(2).To date,numerous attempts have been made to influence the steatohepatitis and liver fibrosis associated with metabolism-associated fatty liver disease(MAFLD)with medication.Nevertheless to date,no substance has been authorised for the indication NAFLD/MAFLD/metabolism-associated steatosis liver disease(MASLD)(3).It has long been known that a consistent change in lifestyle with a reduced diet and physical exercise is able to improve fatty liver disease,steatohepatitis.展开更多
Relevance of liver fibrosis amongst diabetic patients with metabolic-dysfunction associated steatotic liver disease(MASLD)and knowledge gaps Insulin resistance is paramount in the crosstalk between intrahepatic and ex...Relevance of liver fibrosis amongst diabetic patients with metabolic-dysfunction associated steatotic liver disease(MASLD)and knowledge gaps Insulin resistance is paramount in the crosstalk between intrahepatic and extrahepatic pathophysiological mechanisms leading to MASLD(1),hence gaining special relevance in patients diagnosed with type 2 diabetes(T2D).MASLD is the term that was recently endorsed by an international multidisciplinary consensus panel to replace non-alcoholic fatty liver disease[as non-alcoholic steatohepatitis(NASH)was replaced by metabolic dysfunction-associated steatohepatitis(MASH)](2).展开更多
Background:High liver fat content(LFC)induces increased risks of both hepatic and extrahepatic progression in metabolic dysfunction-associated steatotic liver disease(MASLD),while maintaining a significant decline in ...Background:High liver fat content(LFC)induces increased risks of both hepatic and extrahepatic progression in metabolic dysfunction-associated steatotic liver disease(MASLD),while maintaining a significant decline in magnetic resonance imaging-based proton density fat fraction(MRI-PDFF)(≥30%decline relative to baseline)without worsening fibrosis results in improved histological severity and prognosis.However,the factors associated with the loss of sustained responses to treatment remain unclear,and we aim to identify them.Methods:Consecutive treatment-naïve MASLD patients between January 2015 and February 2022,with follow-up until April 2023,were included in this prospective cohort study.LFC quantified by MRI-PDFF and liver stiffness measurements(LSM)determined by two-dimensional shear wave elastography(2D-SWE)were evaluated at weeks 0,24 and 48.MRI-PDFF response was defined as a≥30%relative decline in PDFF values,and LSM response was defined as a≥1 stage decline from baseline.Results:A total of 602 MASLD patients were enrolled.Of the 303 patients with a 24-week MRI-PDFF response and complete follow-up of 48 weeks,the rate of loss of MRI-PDFF response was 29.4%,and multivariable logistic regression analyses showed that 24-week insulin resistance(IR),still regular exercise and caloric restriction after 24 weeks,and the relative decline in LFC were risk factors for loss of MRI-PDFF response.Loss of LSM response at 48 weeks occurred in 15.9%of patients,and multivariable analysis confirmed 24-week serum total bile acid(TBA)levels and the relative decline in TBA from baseline as independent predictors.No significant association was found at 48 weeks between loss of MRI-PDFF response and loss of LSM response.Conclusions:MASLD patients with IR and high TBA levels are at higher risks of subsequent diminished sustained improvements of steatosis and fibrosis,respectively.展开更多
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.
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.
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 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 the National Natural Science Foundation of China(Nos.81930109,82321005,82073926,82373946 and 82073928)the Major State Basic Research DevelopmentProgramofChina(Nos.2021YFA1301300and 2022YFA1303800)+3 种基金Overseas Expertise Introduction Project for Discipline Innovation(No.G20582017001)the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University(Nos.SKLNMZZ202202 and SKLNMZZ202402)the Fundamental Research Funds for the Central Universities(No.2632023TD10)the Project Program of Basic Science Research Center Base(Pharmaceutical Science)of Yantai University(No.Y202204).
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most prevalent chronic liver disease globally,with only one Food and Drug Administration(FDA)-approved drug for its treatment.Given MASLD's complex pathophysiology,ther-apies that simultaneously target multiple pathways are highly desirable.One promising approach is dual-modulation of the famesoid X receptor(FXR),which regulates lipid and bile acid metabolism.However,FXR agonists alone are insufficient due to their limited anti-inflammatory effects.This study aimed to dto identify natural products capable of both FXR activation and inflammation inhibition to provide a comprehensive therapeutic approach for MASLD.Potential FXR ligands from the Natural Product Library were predicted via virtual screening using the Protein Preparation Wizard module in Schrodinger(2018)for molecular docking.Direct binding and regulation of candidate compounds on FXR were analyzed using surface plasmon resonance(SPR)binding assay,reporter gene ana-lysis,and reverse transcription-polymerase chain reaction(RT-PCR).The anti-inflammatory properties of these compounds were eval-uated in AML12 cells treated with tumor necrosis factor-alpha(TNF-α).Dual-function compounds with FXR agonism and inflamma-tion inhibition were further identified in cells transfected with Fxr siRNA and treated with TNF-α.The effects of these dual-function compounds on lipid accumulation and inflammation were evaluated in cells treated with palmitic acid.Results revealed that 17 natural products were predicted via computational molecular docking as potential FXR agonists,with 15 exhibiting a strong affinity for FXR recombinant protein.Nine isoflavone compounds significantly enhanced FXR reporter luciferase activity and the mRNA expressions of Shp and Ostb.Structure-activity relationship analysis indicated that introducing isopropyl or methoxy groups at the C7 position or a methoxy group at the C6 position could enhance the agonistic efficacy of isoflavones.Three compounds(2,6,and 8)were identified as dual-function natural products functioning as FXR agonists and inflammatory inhibitors,while one compound(12)acted as an FXR agonist to inhibit inflammation.These natural products protected hepatocytes against palmitic acid-induced lipid accumulation and in-flammation.In conclusion,compounds 2,6,and 8(genistein,biochanin A,and 7-methoxyisoflavone,respectively)were identified as dual-function bioactive products that transactivate FXR and inhibit inflammation,serving as potential candidates or lead compounds for MASLD therapy.
基金supported by the Shanghai Jiao Tong University School of Medicine Digestive Academy of Science Grant(KY-2023-04-01)to YH.
文摘Given the global prevalence and rising incidence of metabolic dysfunction-associated steatotic liver disease(MASLD),the absence of licensed medications is striking.A deeper understanding of the heterogeneous nature of MASLD has recently contributed to the discovery of novel groups of agents and the potential repurposing of currently available medications.MASLD therapies center on four major pathways.Considering the close relationship between MASLD and type 2 diabetes,the first approach involves antidiabetic medications,including incretins,thiazolidinedione insulin sensitizers,and sodium-glucose cotransporter 2 inhibitors.The second approach targets hepatic lipid accumulation and the resultant metabolic stress.Agents in this group include peroxisome proliferatoractivated receptor agonists(e.g.,pioglitazone,elafibranor,saroglitazar),bile acid-farnesoid X receptor axis regulators(obeticholic acid),de novo lipogenesis inhibitors(aramchol,NDI-010976),and fibroblast growth factor 21/19 analogs.The third approach focuses on targeting oxidative stress,inflammation,and fibrosis.Agents in this group include antioxi-dants(vitamin E),tumor necrosis factor a pathway regulators(emricasan,pentoxifylline,ZSP1601),and immune modulators(cenicriviroc,belapectin).The final group targets the gut(IMM-124e,solithromycin).Combination therapies targeting different pathogenetic pathways may provide an alternative to MASLD treatment with higher efficacy and fewer side effects.This review aimed to provide an update on these medications.
文摘Sarcopenia is a well-known complication of chronic liver disease(CLD),and it is almost always observed in patients with cirrhosis,at least in those with decompensated disease.Since nonalcoholic fatty liver disease(NAFLD),recently renamed metabolic dysfunction-associated steatotic liver disease(MASLD),is becoming the leading cause of end-stage liver disease,a new scenario characterized by the frequent coexistence of NAFLD,obesity,and sarcopenia is emerging.Although it is not yet resolved whether the bidirectional relationship between sarcopenia and NAFLD subtends causal determinants,it is clear that the interaction of these two conditions is associated with an increased risk of poor outcomes.Notably,during the course of CLD,deregulation of the liver-muscle-adipose tissue axis has been described.Unfortunately,owing to the lack of properly designed studies,specific therapeutic guidelines for patients with sarcopenia in the context of NAFLD-related CLD have not yet been defined.Strategies aimed to induce the loss of fat mass together with the maintenance of lean body mass seem most appropriate.This can be achieved by properly designed diets integrated with specific nutritional supplementations and accompanied by adequate physical exercise.Future studies aiming to add to the knowledge of the correct assessment and approach to sarcopenia in the context of NAFLD-related CLD are eagerly awaited.
基金supported by the Research Start-up Funding for the First Affiliated Hospital of USTC(RC2021012)the Fundamental Research Funds for Central Universities(WK9110000004).
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD),formerly known as non-alcoholic fatty liver disease,has a high global prevalence and can progress to metabolic dysfunction-associated steatohepatitis,cirrhosis,and hepatocellular carcinoma.The pathogenesis of MASLD is primarily driven by disturbances in hepatic lipid metabolism,involving six key processes:increased hepatic fatty acid uptake,enhanced fatty acid synthesis,reduced oxidative degradation of fatty acids,increased cholesterol uptake,elevated cholesterol synthesis,and increased bile acid synthesis.Consequently,maintaining hepatic lipid metabolic homeostasis is essential for effective MASLD management.Numerous novel molecules and Chinese proprietary medicines have demonstrated promising therapeutic potential in treating MASLD,primarily by inhibiting lipid synthesis and promoting lipid oxidation.In this review,we summarized recent research on MASLD,elucidated the molecular mechanisms by which lipid metabolism disorders contribute to MASLD pathogenesis,and discussed various lipid metabolism-targeted therapeutic approaches for MASLD.
基金supported by the SERB(CRC/2022/002149)Wellcome Trust/DBT India Alliance Fellowship[IA/I/16/2/502691].
文摘The onset of metabolic dysfunction-associated steatohepatitis(MASH)or non-alcoholic steatohepatitis(NASH)represents a tipping point leading to liver injury and subsequent hepatic complications in the natural progression of what is now termed metabolic dysfunction-associated steatotic liver diseases(MASLD),formerly known as non-alcoholic fatty liver disease(NAFLD).With no pharmacological treat-ment currently available for MASH/NASH,the race is on to develop drugs targeting multiple facets of hepatic metabolism,inflammation,and pro-fibrotic events,which are major drivers of MASH.Nuclear receptors(NRs)regulate genomic transcription upon binding to lipophilic ligands and govern multiple aspects of liver metabolism and inflammation.Ligands of NRs may include hormones,lipids,bile acids,and synthetic ligands,which upon binding to NRs regulate the transcriptional activities of target genes.NR ligands are presently the most promising drug candidates expected to receive approval from the United States Food and Drug Administration as a pharmacological treatment for MASH.This review aims to cover the current understanding of NRs,including nuclear hormone receptors,non-steroid hormone receptors,circadian NRs,and orphan NRs,which are currently undergoing clinical trials for MASH treatment,along with NRs that have shown promising results in preclinical studies.
文摘Metabolic-dysfunction associated steatotic liver disease(MASLD),formerly known as non-alcoholic fatty liver disease(NAFLD)(1),is characterized by the accumulation of fat in the liver cells,independent of excessive alcohol consumption and has emerged as the most prevalent chronic liver condition in Western countries,underscoring a significant public health concern(2).The progression of MASLD to advanced fibrosis,marked by excessive extracellular matrix deposition and scar tissue formation,is a critical stage in MASLD natural history that significantly increases the risk of liver-related complications mortality(3).Non-invasive tests(NITs),such as liver stiffness measurement(LSM)with transient elastography(TE)and serum biomarkers,have gained prominence for assessing liver fibrosis in patients with suspected/confirmed NAFLD,offering a safer and less invasive alternative to liver biopsy(4).
文摘We read with great interest the informative study by Armandi et al.,which shed light on the potential role of serum ferritin in predicting the long-term prognosis of patients with metabolic dysfunction-associated steatotic liver disease(1).However,there remain certain facets requiring in-depth investigation and interpretation.First of all,the study found that integrating stepwise increased ferritin thresholds(215.5 and 272µg/L)into predictive models can improve the performance of fibrosis-4(FIB-4)and Non-Alcoholic Fatty Liver Disease Fibrosis Score(NFS)in the longitudinal risk assessment of liver-related events and overall mortality.However,it has been suggested that metabolic hyperferritinaemia(MHF)appears to exhibit a male predominance(2,3).Since the study primarily comprised male participants(65%),it raises the query of whether the ferritin threshold based on the entire population can accurately predict risks within female patients.Therefore,a sex-specific analysis is warranted to ensure a more precise evaluation.
基金funded by the German Research Foundation(DFGgrants DFG AZ RO957/13-1).
文摘Liver disease associated with metabolic dysfunction now affects more than 30%of the world’s population(1).Historically known as non-alcoholic fatty liver disease(NAFLD)is caused by obesity,lack of exercise,and a westernised lifestyle(2).To date,numerous attempts have been made to influence the steatohepatitis and liver fibrosis associated with metabolism-associated fatty liver disease(MAFLD)with medication.Nevertheless to date,no substance has been authorised for the indication NAFLD/MAFLD/metabolism-associated steatosis liver disease(MASLD)(3).It has long been known that a consistent change in lifestyle with a reduced diet and physical exercise is able to improve fatty liver disease,steatohepatitis.
文摘Relevance of liver fibrosis amongst diabetic patients with metabolic-dysfunction associated steatotic liver disease(MASLD)and knowledge gaps Insulin resistance is paramount in the crosstalk between intrahepatic and extrahepatic pathophysiological mechanisms leading to MASLD(1),hence gaining special relevance in patients diagnosed with type 2 diabetes(T2D).MASLD is the term that was recently endorsed by an international multidisciplinary consensus panel to replace non-alcoholic fatty liver disease[as non-alcoholic steatohepatitis(NASH)was replaced by metabolic dysfunction-associated steatohepatitis(MASH)](2).
基金National Natural Science Foundation of China(grant Nos.81870404 and 82100648)Natural Science Foundation of Guangdong Province,China(grant Nos.2021A1515011442 and 2022A1515012369)China Postdoctoral Science Foundation(grant No.2020M683128).
文摘Background:High liver fat content(LFC)induces increased risks of both hepatic and extrahepatic progression in metabolic dysfunction-associated steatotic liver disease(MASLD),while maintaining a significant decline in magnetic resonance imaging-based proton density fat fraction(MRI-PDFF)(≥30%decline relative to baseline)without worsening fibrosis results in improved histological severity and prognosis.However,the factors associated with the loss of sustained responses to treatment remain unclear,and we aim to identify them.Methods:Consecutive treatment-naïve MASLD patients between January 2015 and February 2022,with follow-up until April 2023,were included in this prospective cohort study.LFC quantified by MRI-PDFF and liver stiffness measurements(LSM)determined by two-dimensional shear wave elastography(2D-SWE)were evaluated at weeks 0,24 and 48.MRI-PDFF response was defined as a≥30%relative decline in PDFF values,and LSM response was defined as a≥1 stage decline from baseline.Results:A total of 602 MASLD patients were enrolled.Of the 303 patients with a 24-week MRI-PDFF response and complete follow-up of 48 weeks,the rate of loss of MRI-PDFF response was 29.4%,and multivariable logistic regression analyses showed that 24-week insulin resistance(IR),still regular exercise and caloric restriction after 24 weeks,and the relative decline in LFC were risk factors for loss of MRI-PDFF response.Loss of LSM response at 48 weeks occurred in 15.9%of patients,and multivariable analysis confirmed 24-week serum total bile acid(TBA)levels and the relative decline in TBA from baseline as independent predictors.No significant association was found at 48 weeks between loss of MRI-PDFF response and loss of LSM response.Conclusions:MASLD patients with IR and high TBA levels are at higher risks of subsequent diminished sustained improvements of steatosis and fibrosis,respectively.
