This article comments on the work by Soresi and Giannitrapani.The authors have stated that one of the most novel and promising treatments for metabolic dysfunction-associated steatotic liver disease(MASLD)is the use o...This article comments on the work by Soresi and Giannitrapani.The authors have stated that one of the most novel and promising treatments for metabolic dysfunction-associated steatotic liver disease(MASLD)is the use of glucagon-like peptide 1 receptor agonists,especially when used in combination therapy.However,despite their notable efficacy,these drugs were not initially designed to target MASLD directly.In a groundbreaking development,the Food and Drug Administration has recently approved resmetirom,the first treatment specifically aimed at reducing liver fibrosis in metabolic-associated steatohepatitis.Resmetirom,an orally administered,liver-directed thyroid hormone beta-selective agonist,acts directly on intrahepatic pathways,enhancing its therapeutic potential and marking the beginning of a new era in the treatment of MASLD.Furthermore,the integration of lifestyle modifications into liver disease management is an essential component that should be considered and reinforced.By incorporating dietary changes and regular physical exercise into treatment,patients may achieve improved outcomes,reducing the need for pharmacological interventions and/or improving treatment efficacy.As a complement to medical therapies,lifestyle factors should not be overlooked in the broader strategy for managing MASLD.展开更多
Psoriasis is a prevalent inflammatory disease that shares chronic inflammation pathways with the pathophysiology of metabolic syndrome(MetS),type-2 diabetes mellitus and atherosclerosis.A high prevalence of steatosis ...Psoriasis is a prevalent inflammatory disease that shares chronic inflammation pathways with the pathophysiology of metabolic syndrome(MetS),type-2 diabetes mellitus and atherosclerosis.A high prevalence of steatosis and advanced liver fibrosis has been described in psoriasis.The influence of MetS and its compounds,patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2 gene polymorphisms and the cumulative dose of methotrexate(MTX)in the progression of steatotic disease are still under debate.A suitable new classification for psoriasis-related liver disease,under the umbrella of steatotic liver disease(SLD),might be evaluated due to the potential impact of MTX on liver steatosis.Considering the interplay between the MetS,steatosis and MTX,a new definition for this complex disease might be discussed since it is not entirely addressed under the umbrella of SLD and metabolic-dysfunction associated SLD.Hence,shortly,a discussion could be raised on the feasible term“Met-Drug SLD”,metabolic and drug-induced SLD,which comprises both metabolic dysfunction and drug-related SLD.This review aims to report the best evidence to accurately classify liver disease in psoriasis,considering the new definition of SLD,allowing appropriate management once it is carefully defined.展开更多
Metabolic dysfunction-associated fatty liver disease(MAFLD)is a new acronym adopted from the consensus of international experts.Given the increasing prevalence of MAFLD in pre-transplant settings,de novo and recurrent...Metabolic dysfunction-associated fatty liver disease(MAFLD)is a new acronym adopted from the consensus of international experts.Given the increasing prevalence of MAFLD in pre-transplant settings,de novo and recurrent graft steatosis/MAFLD are common in post-transplant settings.The impact of graft steatosis on long-term outcomes is unclear.The current knowledge of incidence rate,risk factors,diagnosis,long-term outcomes,and management of graft steatosis(both de novo and recurrent)is discussed in this review.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)is currently a pressing public health issue associated with adverse outcomes such as cirrhosis,malignancy,transplantation,and mortality.Lifestyle modifica...Metabolic dysfunction-associated steatotic liver disease(MASLD)is currently a pressing public health issue associated with adverse outcomes such as cirrhosis,malignancy,transplantation,and mortality.Lifestyle modifications constitute the most effective and fundamental management approach,but they often pose challenges in sustaining long-term clinical benefits.Hence,there is a critical need to enhance our understanding through pharmacological management,which unfortunately remains limited.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)have emerged as a leading treatment in the fields of diabetes and obesity,with recent preclinical and clinical studies indicating significant benefits in the management and treatment of MASLD.Our article begins by reviewing the beneficial therapeutic components of GLP-1RAs in MASLD.Subsequently,from a clinical research perspective,we concluded with the liver outcomes of current primary GLP-1RAs and co-agonists.Finally,we presented our insights on clinical concerns such as appropriate trial endpoints,management of comorbidities,and future developments.In conclusion,the benefits of GLP-1RAs in MASLD are promising,and background therapy involving metabolic modulation may represent one of the future therapeutic paradigms.展开更多
Background and Aims:Metabolic dysfunction-associated steatotic liver disease(MASLD),is the most common form of chronic liver disease worldwide.This study aimed to explore the role of TM6SF2 in high-fat diet(HFD)-induc...Background and Aims:Metabolic dysfunction-associated steatotic liver disease(MASLD),is the most common form of chronic liver disease worldwide.This study aimed to explore the role of TM6SF2 in high-fat diet(HFD)-induced MASLD through the gut-liver axis.Methods:The TM6SF2 gut-specific knockout(TM6SF2 GKO)mouse was constructed using CRISPR/Cas9 technology.TM6SF2 GKO and wild-type(CON)mice were fed either a HFD or a control diet for 16 weeks to induce MASLD.Blood,liver,and intestinal lipid content,as well as gut microbiota and serum metabolites,were then analyzed.Results:TM6SF2 GKO mice fed an HFD showed elevated liver and intestinal lipid deposition compared to CON mice.The gut microbiota of HFD-fed TM6SF2 GKO mice exhibited a decreased Firmicutes/Bacteroidetes ratio compared to HFD-fed CON mice.The HFD also reduced the diversity and abundance of the microbiota and altered its composition.Aspartate aminotransferase,alanineaminotransferase,and total cholesterol levels were higher in HFD-fed TM6SF2 GKO mice compared to CON mice,while triglyceride levels were lower.Serum metabolite analysis revealed that HFDfed TM6SF2 GKO mice had an increase in the expression of 17 metabolites(e.g.,LPC[18:0/0-0])and a decrease in 22 metabolites(e.g.,benzene sulfate).The differential metabolites of LPC(18:0/0-0)may serve as HFD-fed TM6SF2 serum biomarkers,leading to MASLD exacerbation in GKO mice.Conclusions:TM6SF2 GKO aggravates liver lipid accumulation and liver injury in MASLD mice.TM6SF2 may play an important role in regulating intestinal flora and the progression of MASLD through the gut-liver axis.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)has become a global epidemic,yet effective pharmacological treatments remain limited.Secreted proteins play diverse roles in regulating glucose and lipid ...Metabolic dysfunction-associated steatotic liver disease(MASLD)has become a global epidemic,yet effective pharmacological treatments remain limited.Secreted proteins play diverse roles in regulating glucose and lipid metabolism,and their dysregulation is implicated in the development of various metabolic diseases,including MASLD.Therefore,targeting secreted proteins and modulating associated signaling pathways represents a promising therapeutic strategy for MASLD.In this review,we summarize recent findings on the roles of emerging families of secreted proteins in MASLD and related metabolic disorders.These include the orosomucoid(ORM)family,secreted acidic cysteine rich glycoprotein(SPARC)family,neuregulin(Nrg)family,growth differentiation factor(GDF)family,interleukin(IL)family,fibroblast growth factor(FGF)family,bone morphogenic protein(BMP)family,as well as isthmin-1(Ism1)and mesencephalic astrocyte-derived neurotrophic factor(MANF).The review highlights their impact on glucose and lipid metabolism and discusses the clinical potential of targeting these secreted proteins as a therapeutic approach for MASLD.展开更多
Metabolic dysfunction-associated fatty liver disease(MAFLD)has reached epidemic proportions globally in parallel to the rising prevalence of obesity.Despite its significant burden,there is no approved pharmacotherapy ...Metabolic dysfunction-associated fatty liver disease(MAFLD)has reached epidemic proportions globally in parallel to the rising prevalence of obesity.Despite its significant burden,there is no approved pharmacotherapy specifically tailored for this disease.Many potential drug candidates for MAFLD have encountered setbacks in clinical trials,due to safety concerns or/and insufficient therapeutic efficacy.Nonetheless,several investigational drugs that mimic the actions of endogenous metabolic hormones,including thyroid hormone receptorβ(THRβ)agonists,fibroblast growth factor 21(FGF21)analogues,and glucagon-like peptide-1 receptor agonists(GLP-1RAs),showed promising therapeutic efficacy and excellent safety profiles.Among them,resmetirom,a liver-targeted THRβ-selective agonist,has met the primary outcomes in alleviation of metabolic dysfunction-associated steatohepatitis(MASH),the advanced form of MAFLD,and liver fibrosis in phase-3 clinical trials.These hormone-based pharmacotherapies not only exhibit varied degrees of therapeutic efficacy in mitigating hepatic steatosis,inflammation and fibrosis,but also improve metabolic profiles.Furthermore,these three hormonal agonists/analogues act in a complementary manner to exert their pharmacological effects,suggesting their combined therapies may yield synergistic therapeutic benefits.Further in-depth studies on the intricate interplay among these metabolic hormones are imperative for the development of more efficacious combination therapies,enabling precision management of MAFLD and its associated comorbidities.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)is defined as hepatic steatosis with at least one concomitant cardiovascular risk factor,and has emerged as the most frequent liver disease worldwide(1).I...Metabolic dysfunction-associated steatotic liver disease(MASLD)is defined as hepatic steatosis with at least one concomitant cardiovascular risk factor,and has emerged as the most frequent liver disease worldwide(1).It conveys risks of liver disease progression to metabolic dysfunction-associated steatohepatitis(MASH)and of cardiovascular events(2).展开更多
Bilirubin,the primary breakdown product of hemoproteins,particularly hemoglobin,plays a key role in the diagnosis,prognosis,and monitoring of liver diseases.In acute liver dis-eases,such as acute liver failure,drug-in...Bilirubin,the primary breakdown product of hemoproteins,particularly hemoglobin,plays a key role in the diagnosis,prognosis,and monitoring of liver diseases.In acute liver dis-eases,such as acute liver failure,drug-induced liver injury,and viral hepatitis,bilirubin serves as a biomarker reflecting the extent of hepatocyte loss and liver damage.Chronic liver diseases,including alcohol-related liver disease,chronic hep-atitis C virus infection,metabolic dysfunction-associated fat-ty liver disease,and autoimmune liver diseases,are marked by persistent liver injury and inflammation.Bilirubin levels in chronic liver diseases provide insight into liver function,disease severity,and prognosis.As a versatile biomarker,bilirubin offers valuable information on the pathophysiology of liver diseases and aids in guiding clinical decision-making regarding the treatment of liver diseases and their complica-tions.This review aimed to explore the multifunctional role of bilirubin in liver diseases by analyzing its biological functions beyond its role as a biomarker of liver damage.展开更多
文摘This article comments on the work by Soresi and Giannitrapani.The authors have stated that one of the most novel and promising treatments for metabolic dysfunction-associated steatotic liver disease(MASLD)is the use of glucagon-like peptide 1 receptor agonists,especially when used in combination therapy.However,despite their notable efficacy,these drugs were not initially designed to target MASLD directly.In a groundbreaking development,the Food and Drug Administration has recently approved resmetirom,the first treatment specifically aimed at reducing liver fibrosis in metabolic-associated steatohepatitis.Resmetirom,an orally administered,liver-directed thyroid hormone beta-selective agonist,acts directly on intrahepatic pathways,enhancing its therapeutic potential and marking the beginning of a new era in the treatment of MASLD.Furthermore,the integration of lifestyle modifications into liver disease management is an essential component that should be considered and reinforced.By incorporating dietary changes and regular physical exercise into treatment,patients may achieve improved outcomes,reducing the need for pharmacological interventions and/or improving treatment efficacy.As a complement to medical therapies,lifestyle factors should not be overlooked in the broader strategy for managing MASLD.
文摘Psoriasis is a prevalent inflammatory disease that shares chronic inflammation pathways with the pathophysiology of metabolic syndrome(MetS),type-2 diabetes mellitus and atherosclerosis.A high prevalence of steatosis and advanced liver fibrosis has been described in psoriasis.The influence of MetS and its compounds,patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2 gene polymorphisms and the cumulative dose of methotrexate(MTX)in the progression of steatotic disease are still under debate.A suitable new classification for psoriasis-related liver disease,under the umbrella of steatotic liver disease(SLD),might be evaluated due to the potential impact of MTX on liver steatosis.Considering the interplay between the MetS,steatosis and MTX,a new definition for this complex disease might be discussed since it is not entirely addressed under the umbrella of SLD and metabolic-dysfunction associated SLD.Hence,shortly,a discussion could be raised on the feasible term“Met-Drug SLD”,metabolic and drug-induced SLD,which comprises both metabolic dysfunction and drug-related SLD.This review aims to report the best evidence to accurately classify liver disease in psoriasis,considering the new definition of SLD,allowing appropriate management once it is carefully defined.
文摘Metabolic dysfunction-associated fatty liver disease(MAFLD)is a new acronym adopted from the consensus of international experts.Given the increasing prevalence of MAFLD in pre-transplant settings,de novo and recurrent graft steatosis/MAFLD are common in post-transplant settings.The impact of graft steatosis on long-term outcomes is unclear.The current knowledge of incidence rate,risk factors,diagnosis,long-term outcomes,and management of graft steatosis(both de novo and recurrent)is discussed in this review.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is currently a pressing public health issue associated with adverse outcomes such as cirrhosis,malignancy,transplantation,and mortality.Lifestyle modifications constitute the most effective and fundamental management approach,but they often pose challenges in sustaining long-term clinical benefits.Hence,there is a critical need to enhance our understanding through pharmacological management,which unfortunately remains limited.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)have emerged as a leading treatment in the fields of diabetes and obesity,with recent preclinical and clinical studies indicating significant benefits in the management and treatment of MASLD.Our article begins by reviewing the beneficial therapeutic components of GLP-1RAs in MASLD.Subsequently,from a clinical research perspective,we concluded with the liver outcomes of current primary GLP-1RAs and co-agonists.Finally,we presented our insights on clinical concerns such as appropriate trial endpoints,management of comorbidities,and future developments.In conclusion,the benefits of GLP-1RAs in MASLD are promising,and background therapy involving metabolic modulation may represent one of the future therapeutic paradigms.
基金funded by The National Natural Science Foundation of China(NSFC,No.82100618)the China Postdoctoral Science Foundation(No.2021M701820).
文摘Background and Aims:Metabolic dysfunction-associated steatotic liver disease(MASLD),is the most common form of chronic liver disease worldwide.This study aimed to explore the role of TM6SF2 in high-fat diet(HFD)-induced MASLD through the gut-liver axis.Methods:The TM6SF2 gut-specific knockout(TM6SF2 GKO)mouse was constructed using CRISPR/Cas9 technology.TM6SF2 GKO and wild-type(CON)mice were fed either a HFD or a control diet for 16 weeks to induce MASLD.Blood,liver,and intestinal lipid content,as well as gut microbiota and serum metabolites,were then analyzed.Results:TM6SF2 GKO mice fed an HFD showed elevated liver and intestinal lipid deposition compared to CON mice.The gut microbiota of HFD-fed TM6SF2 GKO mice exhibited a decreased Firmicutes/Bacteroidetes ratio compared to HFD-fed CON mice.The HFD also reduced the diversity and abundance of the microbiota and altered its composition.Aspartate aminotransferase,alanineaminotransferase,and total cholesterol levels were higher in HFD-fed TM6SF2 GKO mice compared to CON mice,while triglyceride levels were lower.Serum metabolite analysis revealed that HFDfed TM6SF2 GKO mice had an increase in the expression of 17 metabolites(e.g.,LPC[18:0/0-0])and a decrease in 22 metabolites(e.g.,benzene sulfate).The differential metabolites of LPC(18:0/0-0)may serve as HFD-fed TM6SF2 serum biomarkers,leading to MASLD exacerbation in GKO mice.Conclusions:TM6SF2 GKO aggravates liver lipid accumulation and liver injury in MASLD mice.TM6SF2 may play an important role in regulating intestinal flora and the progression of MASLD through the gut-liver axis.
基金supported by the National Natural Science Foundation of China(92268109,82325010,82273167,82400937).
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)has become a global epidemic,yet effective pharmacological treatments remain limited.Secreted proteins play diverse roles in regulating glucose and lipid metabolism,and their dysregulation is implicated in the development of various metabolic diseases,including MASLD.Therefore,targeting secreted proteins and modulating associated signaling pathways represents a promising therapeutic strategy for MASLD.In this review,we summarize recent findings on the roles of emerging families of secreted proteins in MASLD and related metabolic disorders.These include the orosomucoid(ORM)family,secreted acidic cysteine rich glycoprotein(SPARC)family,neuregulin(Nrg)family,growth differentiation factor(GDF)family,interleukin(IL)family,fibroblast growth factor(FGF)family,bone morphogenic protein(BMP)family,as well as isthmin-1(Ism1)and mesencephalic astrocyte-derived neurotrophic factor(MANF).The review highlights their impact on glucose and lipid metabolism and discusses the clinical potential of targeting these secreted proteins as a therapeutic approach for MASLD.
基金supported by National Key R&D Program of China(2022YFA0806102)the Hong Kong Research Grants Council/Area of Excellence(AoE/M-707/18)+2 种基金Health and Medical Research Fund(06172446)General Research Fund(17127518)as well as the National Natural Science Foundation of China(82070860,82161138026).
文摘Metabolic dysfunction-associated fatty liver disease(MAFLD)has reached epidemic proportions globally in parallel to the rising prevalence of obesity.Despite its significant burden,there is no approved pharmacotherapy specifically tailored for this disease.Many potential drug candidates for MAFLD have encountered setbacks in clinical trials,due to safety concerns or/and insufficient therapeutic efficacy.Nonetheless,several investigational drugs that mimic the actions of endogenous metabolic hormones,including thyroid hormone receptorβ(THRβ)agonists,fibroblast growth factor 21(FGF21)analogues,and glucagon-like peptide-1 receptor agonists(GLP-1RAs),showed promising therapeutic efficacy and excellent safety profiles.Among them,resmetirom,a liver-targeted THRβ-selective agonist,has met the primary outcomes in alleviation of metabolic dysfunction-associated steatohepatitis(MASH),the advanced form of MAFLD,and liver fibrosis in phase-3 clinical trials.These hormone-based pharmacotherapies not only exhibit varied degrees of therapeutic efficacy in mitigating hepatic steatosis,inflammation and fibrosis,but also improve metabolic profiles.Furthermore,these three hormonal agonists/analogues act in a complementary manner to exert their pharmacological effects,suggesting their combined therapies may yield synergistic therapeutic benefits.Further in-depth studies on the intricate interplay among these metabolic hormones are imperative for the development of more efficacious combination therapies,enabling precision management of MAFLD and its associated comorbidities.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is defined as hepatic steatosis with at least one concomitant cardiovascular risk factor,and has emerged as the most frequent liver disease worldwide(1).It conveys risks of liver disease progression to metabolic dysfunction-associated steatohepatitis(MASH)and of cardiovascular events(2).
文摘Bilirubin,the primary breakdown product of hemoproteins,particularly hemoglobin,plays a key role in the diagnosis,prognosis,and monitoring of liver diseases.In acute liver dis-eases,such as acute liver failure,drug-induced liver injury,and viral hepatitis,bilirubin serves as a biomarker reflecting the extent of hepatocyte loss and liver damage.Chronic liver diseases,including alcohol-related liver disease,chronic hep-atitis C virus infection,metabolic dysfunction-associated fat-ty liver disease,and autoimmune liver diseases,are marked by persistent liver injury and inflammation.Bilirubin levels in chronic liver diseases provide insight into liver function,disease severity,and prognosis.As a versatile biomarker,bilirubin offers valuable information on the pathophysiology of liver diseases and aids in guiding clinical decision-making regarding the treatment of liver diseases and their complica-tions.This review aimed to explore the multifunctional role of bilirubin in liver diseases by analyzing its biological functions beyond its role as a biomarker of liver damage.
