Metabolic dysfunction-associated fatty liver disease(MAFLD)now affects roughly one-quarter of the world’s population,reflecting the global spread of obesity and insulin resistance.Reframing non-alcoholic fatty liver ...Metabolic dysfunction-associated fatty liver disease(MAFLD)now affects roughly one-quarter of the world’s population,reflecting the global spread of obesity and insulin resistance.Reframing non-alcoholic fatty liver disease as MAFLD emphasizes its metabolic roots and spotlights the gut-liver axis,where intestinal dysbiosis acts as a key driver of hepatic injury.Altered microbial com-munities disrupt epithelial integrity,promote bacterial translocation,and trigger endotoxin-mediated inflammation that accelerates steatosis,lipotoxicity,and fibrogenesis.Concurrent shifts in bile acid signaling and short-chain fatty acid profiles further impair glucose and lipid homeostasis,amplifying cardiometabolic risk.Epidemiological studies reveal pervasive dysbiosis in MAFLD cohorts,linked to diet quality,sedentary behavior,adiposity,and host genetics.Newly developed microbiome-derived biomarkers,advanced elastography,and integrated multi-omics panels hold promise for non-invasive diagnosis and stratification,although external validation remains limited.In early trials,interventions that re-engineer the microbiota including tailored pre-/pro-/synbiotics,rational diet patterns,next-generation fecal microbiota transplantation,and bile-acid-modulating drugs show encouraging histological and metabolic gains.Optimal care will likely couple these tools with weight-centered lifestyle programmes in a pre-cision-medicine framework.Key challenges include inter-ethnic variability in microbiome signatures,the absence of consensus treatment algorithms,and regulatory barriers to live biotherapeutics.Rigorous longitudinal studies are required to translate mechanistic insight into durable clinical benefit and improve patient-centered outcome measures.展开更多
Metabolic associated fatty liver disease(MAFLD),formerly named non-alcoholic fatty liver disease is the most common liver disorder in many countries.The inflammatory subtype termed steatohepatitis is a driver of disea...Metabolic associated fatty liver disease(MAFLD),formerly named non-alcoholic fatty liver disease is the most common liver disorder in many countries.The inflammatory subtype termed steatohepatitis is a driver of disease progression to cirrhosis,hepatocellular carcinoma,liver transplantation,and death,but also to extrahepatic complications including cardiovascular disease,diabetes and chronic kidney disease.The plasticity of macrophages in response to various environmental cues and the fact that they can orchestrate cross talk between different cellular players during disease development and progression render them an ideal target for drug development.This report reviews recent advances in our understanding of macrophage biology during the entire spectrum of MAFLD including steatosis,inflammation,fibrosis,and hepatocellular carcinoma,as well as for the extra-hepatic manifestations of MAFLD.We discuss the underlying molecular mechanisms of macrophage activation and polarization as well as cross talk with other cell types such as hepatocytes,hepatic stellate cells,and adipose tissue.We conclude with a discussion on the potential translational implications and challenges for macrophage based therapeutics for MAFLD.展开更多
Metabolic changes are inextricably linked to chronic hepatitis C(CHC).Recently polymorphisms in the IFNL3(IL28B)region have been shown to be strongly associated with spontaneous and treatment induced recovery from hep...Metabolic changes are inextricably linked to chronic hepatitis C(CHC).Recently polymorphisms in the IFNL3(IL28B)region have been shown to be strongly associated with spontaneous and treatment induced recovery from hepatitis C virus(HCV)infection.Further,circumstantial evidence suggests a link between IFNL3single nucleotide polymorphisms and lipid metabolism,steatosis and insulin resistance in CHC.The emerging picture suggests that the responder genotypes of IFNL3polymorphisms are associated with a higher serum lipid profile,and less frequent steatosis and insulin resistance.This review analyzes the current data regarding this interaction and its meaning for HCV pathogenesis and disease progression.展开更多
Background and Objective:Obesity is a global health issue closely linked to multiple cardiovascular and metabolic conditions.The renaming of nonalcoholic fatty liver disease(NAFLD)to metabolic dysfunction-associated f...Background and Objective:Obesity is a global health issue closely linked to multiple cardiovascular and metabolic conditions.The renaming of nonalcoholic fatty liver disease(NAFLD)to metabolic dysfunction-associated fatty liver disease(MAFLD)has sparked discussions about renaming nonalcoholic fatty pancreas disease(NAFPD).This narrative review explores the potential benefits and challenges of renaming NAFPD to metabolic dysfunction-associated fatty pancreas disease(MAFPD)and its potential clinical implications.Methods:The review employs a narrative approach,synthesizing existing literature and expert opinions to evaluate the rationale behind and the possible implications of renaming NAFPD to MAFPD.Key Content and Findings:NAFPD is increasingly recognized worldwide but lacks standardized diagnostic criteria,hindering its independent classification as a disease.Renaming NAFPD to MAFPD may enhance diagnostic accuracy,prognostic prediction,and personalized treatment strategies.It may also facilitate global epidemiological research,data sharing,and collaboration.Major challenges include establishing uniform diagnostic guidelines for promoting and educating about the newly proposed terminology.Conclusions:The proposed renaming from NAFPD to MAFPD may offer promising benefits despite challenges.It may also lead to improved management and understanding of the disease,potentially benefiting global healthcare strategies aimed at addressing obesity-related pancreatic complications.展开更多
Metabolic dysfunction-associated fatty liver disease(MAFLD)has become the leading cause of chronic liver disease worldwide,with fibrosis recognized as the main prognostic factor and therapeutic target.While early-stag...Metabolic dysfunction-associated fatty liver disease(MAFLD)has become the leading cause of chronic liver disease worldwide,with fibrosis recognized as the main prognostic factor and therapeutic target.While early-stage fibrosis is reversible,advanced fibrosis poses a significant clinical challenge due to limited treatment options,highlighting the need for innovative management strategies.Recent studies have shown that alternative pre-mRNA splicing,a critical mechanism regulating gene expression and protein diversity,plays a fundamental role in the pathogenesis of MAFLD and associated fibrosis.Understanding the complex relationship between alternative splicing and fibrosis progression in MAFLD could pave the way for novel therapeutic approaches and improve clinical outcomes.In this review,we describe the intricate mechanisms of alternative splicing in fibrosis associated with MAFLD.Specifically,we explored the pivotal of splicing factors,and RNA-binding proteins,highlighting their critical interactions with metabolic and epigenetic regulators.Furthermore,we provide an overview of the latest advancements in splicing-based therapeutic strategies and biomarker development.Particular emphasis is placed on the potential application of antisense oligonucleotides for rectifying splicing anomalies,thereby laying the foundation for precision medicine approaches in the treatment of MAFLDassociated fibrosis.展开更多
The term non-alcoholic fatty liver disease(NAFLD)was coined in 1980 to characterize a disease similar to alcoholic fatty liver disease that developed in patients without a history of excessive alcohol intake.[1]Morpho...The term non-alcoholic fatty liver disease(NAFLD)was coined in 1980 to characterize a disease similar to alcoholic fatty liver disease that developed in patients without a history of excessive alcohol intake.[1]Morphologically,NAFLD is characterized by excess fatty infiltration of the liver in the absence of known causes of liver disease(eg,alcohol,autoimmune liver disease,viral hepatitis,etc).The clinical manifestations of NAFLD(both hepatic and extrahepatic)depend on the outcome of complex interactions between its primary drivers including poor lifestyle habits and diet,a dysfunctional microbiota,genetic predisposition,and environmental cues that result in metabolic dysfunction and liver disease.However,bringing all patients with their markedly different clinical courses under the NAFLD umbrella belies its complexity and implies a homogeneous disease state that then negatively impacts clinical management and a deeper understanding of pathogenesis.With advances in current knowledge on the spectrum of fatty liver diseases,it is apparent that the fourdecade-old outdated term NAFLD can no longer serve to usefully describe a highly heterogeneous disease.The disease as we understand it today not only impacts patients who consume alcohol and those who do not,but also potentially impacts all patients with any form of liver disease,by acting as a disease modifier.[2]展开更多
Background:With the rising global prevalence of fatty liver disease related to metabolic dysfunction,the association of this common liver condition with chronic kidney disease(CKD)has become increasingly evident.In 20...Background:With the rising global prevalence of fatty liver disease related to metabolic dysfunction,the association of this common liver condition with chronic kidney disease(CKD)has become increasingly evident.In 2020,the more inclusive term metabolic dysfunction-associated fatty liver disease(MAFLD)was proposed to replace the term non-alcoholic fatty liver disease(NAFLD).The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD.However,to date,there is no appropriate guidance on CKD in individuals with MAFLD.Furthermore,there has been little attention paid to the link between MAFLD and CKD in the Nephrology community.Methods and Results:Using a Delphi-based approach,a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD.Conclusions:This Delphi-based consensus statement provided guidance on the epidemiology,mechanisms,management and treatment of MAFLD and CKD,as well as the relationship between the severity of MAFLD and risk of CKD,which establish a framework for the early prevention and management of these two common and interconnected diseases.展开更多
The prevalence of metabolic(dysfunction)-associated fatty liver disease(MAFLD)is rapidly increasing and affects up to two billion individuals globally,and this has also resulted in increased risks for cirrhosis,hepato...The prevalence of metabolic(dysfunction)-associated fatty liver disease(MAFLD)is rapidly increasing and affects up to two billion individuals globally,and this has also resulted in increased risks for cirrhosis,hepatocellular carcinoma,and liver transplants.In addition,it has also been linked to extrahepatic consequences,such as cardiovascular disease,diabetes,and various types of cancers.However,only a small proportion of patients with MAFLD develop these complications.Therefore,the identification of high-risk patients is paramount.Liver fibrosis is the major determinant in developing these complications.Although,liver biopsy is still considered the gold standard for the assessment of patients with MAFLD.Because of its invasive nature,among many other limitations,the search for noninvasive biomarkers for MAFLD remains an area of intensive research.In this review,we provide an update on the current and future biomarkers of MAFLD,including a discussion of the associated genetics,epigenetics,microbiota,and metabolomics.We also touch on the next wave of multiomic-based biomarkers.展开更多
Metabolic-associated fatty liver disease(MAFLD)(1),formerly known as non-alcoholic fatty liver disease,is a major causes of liver cirrhosis(2).MAFLD represents a growing global health and economic burden since approxi...Metabolic-associated fatty liver disease(MAFLD)(1),formerly known as non-alcoholic fatty liver disease,is a major causes of liver cirrhosis(2).MAFLD represents a growing global health and economic burden since approximately one in four people have the disease(3).As a consequence,MAFLD-related cirrhosis is expected to become the leading cause for liver failure and liver cancer,and the major indication for liver transplantation this century(3).展开更多
Background and Aims:In Europeans,variants in the hydroxysteroid 17-beta dehydrogenase 13(HSD17B13)gene impact liver histology in metabolic-associated fatty liver disease(MAFLD).The impact of these variants in ethnic C...Background and Aims:In Europeans,variants in the hydroxysteroid 17-beta dehydrogenase 13(HSD17B13)gene impact liver histology in metabolic-associated fatty liver disease(MAFLD).The impact of these variants in ethnic Chinese is unknown.The aim of this study was to investigate the potential associations in Chinese patients.Methods:In total,427 Han Chinese with biopsy-confirmed MAFLD were enrolled.Two single nucleotide polymorphisms in HSD17B13 were genotyped:rs72613567 and rs6531975.Logistic regression was used to test the association between the single nucleotide polymorphisms and liver histology.Results:In our cohort,the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis[odds ratio(OR):2.93(1.20–7.17),p=0.019 for the additive model;OR:3.32(1.39–7.91),p=0.007 for the recessive model],representing an inverse association as compared to the results from European cohorts.In contrast,we observed a protective effect on fibrosis for the minor A allele carriers of the HSD17B13 rs6531975 variant[OR:0.48(0.24–0.98),p=0.043 for the additive model;OR:0.62(0.40–0.94),p=0.025 for the dominant model].HSD17B13 variants were only associated with fibrosis but no other histological features.Furthermore,HSD17B13 rs6531975 modulated the effect of PNPLA3 rs738409 on hepatic steatosis.Conclusions:HSD17B13 rs72613567 is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans.These data exemplify the need for studying diverse populations in genetic studies in order to fine map genome-wide association studies signals.展开更多
The majority of global deaths are attributed to one of the noncommunicable diseases(NCDs),and cancer is projected to be the leading cause of death worldwide in the 21st century(1).There were 18.1 million incident canc...The majority of global deaths are attributed to one of the noncommunicable diseases(NCDs),and cancer is projected to be the leading cause of death worldwide in the 21st century(1).There were 18.1 million incident cancer cases worldwide in 2018,43.8 million are living with cancer and 9.6 million deaths from cancer.One in 6 deaths is due to cancer and these numbers are projected to rise to 13 million by 2030,more than that from tuberculosis,malaria and HIV/AIDS combined.In addition,the total annual global cost of cancer was estimated at around US$1.16 trillion,representing a significant burden on health care systems and families(1).展开更多
Metabolic(dysfunction)-associated fatty liver disease(MAFLD;formerly known as non-alcoholic fatty liver disease)is the most common liver disorder,affecting around one-third of the population worldwide(1).MAFLD is a he...Metabolic(dysfunction)-associated fatty liver disease(MAFLD;formerly known as non-alcoholic fatty liver disease)is the most common liver disorder,affecting around one-third of the population worldwide(1).MAFLD is a heterogeneous disease with a spectrum of liver pathologies that spans from hepatic lipid accumulation(steatosis)to chronic inflammation(steatohepatitis),which can progress to cirrhosis and hepatocellular carcinoma.It is impacted by a myriad of factors,including metabolic health,biological and chronological age,genetics and epigenetics(2-4).However,only a proportion(5-40%)of patients develop liver inflammation or steatohepatitis(5).This transition is a cardinal feature of progressive liver disease,which is the precursor to the development of the hepatic and extra-hepatic outcomes.展开更多
With the widespread increase in energy intake and physical inactivity,the prevalence of metabolic health is declining.Consequently,metabolic associated fatty liver disease(MAFLD)[formerly known as non-alcoholic fatty ...With the widespread increase in energy intake and physical inactivity,the prevalence of metabolic health is declining.Consequently,metabolic associated fatty liver disease(MAFLD)[formerly known as non-alcoholic fatty liver disease(NAFLD)]has risen in prevalence and present a significant challenge to global health causing considerable morbidity and mortality,particularly when fibrosis is present(1).展开更多
Background and Objective:Hepatocellular carcinoma(HCC)poses a significant global health burden and ranks as the fifth most prevalent cancer on a global scale.Hepatitis C virus(HCV)infection remains one of the major ri...Background and Objective:Hepatocellular carcinoma(HCC)poses a significant global health burden and ranks as the fifth most prevalent cancer on a global scale.Hepatitis C virus(HCV)infection remains one of the major risk factors for HCC development.HCC is a heterogeneous disease,and the development of HCC caused by HCV is intricate and involves various factors,including genetic susceptibility,viral factors,immune response due to chronic inflammation,alcohol abuse,and metabolic dysfunction associated with fatty liver disease.In this review,we provide a comprehensive and updated review of research on the genetics and epigenetic mechanisms implicated in developing HCC associated with HCV infection.We also discuss the potential translational implications,including novel biomarkers and drugs for treatment.Methods:A comprehensive literature search was conducted in June 2023 in PubMed and Embase databases.Key Content and Findings:Recent findings indicate that a variety of genetic and epigenetic processes are involved in the pathogenesis and continue to exist even after the complete elimination of HCV.The deregulation of the epigenome has been identified as a significant factor in the deletrious effects of liver disease,especially during the initial stages when genetic alterations are uncommon.The enduring“epigenetic memory”of gene expression is believed to be regulated by epigenetic mechanisms,indicating that alterations caused by HCV infection continue to exist and are linked to the risk of development of liver cancer even after successful treatment.Systems biology analytical methods will be required to delineate the magnitude and significance of both genetic and epigenomic alterations in tumor evolution.Conclusions:By facilitating a more profound understanding of these aspects,this will ultimately foster the advancement of novel therapies and ultimately improve outcomes for patients.展开更多
To provide clarity for research studies and clinical care,a set of positive criteria for adults and children with metabolic(dysfunction)associated fatty liver disease(MAFLD)was recently published and has subsequently ...To provide clarity for research studies and clinical care,a set of positive criteria for adults and children with metabolic(dysfunction)associated fatty liver disease(MAFLD)was recently published and has subsequently been widely endorsed.The development and subsequent validation of the criteria for MAFLD has created a positive momentum for change.During the course of the ongoing discussion on the redefinition,some concerns have surfaced that we thought needs clarification.In this review,we provide a perspective on MAFLD and bringing clarity to some of the key aspects that have been recently raised.展开更多
As of today,March 30,2020,when this Editorial is being written,the severe acute respiratory syndrome coronavirus-2(SARS-CoV-2),causal agent of the coronavirus disease(COVID-19)has been confirmed in more than 745,000 c...As of today,March 30,2020,when this Editorial is being written,the severe acute respiratory syndrome coronavirus-2(SARS-CoV-2),causal agent of the coronavirus disease(COVID-19)has been confirmed in more than 745,000 cases worldwide and has claimed the lives of more than 35,000 people.1 In addition to the morbidity and mortality associated with COVID-19,this betacoronavirus has placed several of the world's major economies in strife,mainly in Western Europe and North America,paralyzing travel and regular social interactions,making COVID-19 undoubtedly one of the most important pandemics in human history.展开更多
Metabolic dysfunction-associated fatty liver disease(MAFLD)is a complex,heterogenous and progressive disease that is characterised by substantial phenotypic variability,which results in disparate clinical presentation...Metabolic dysfunction-associated fatty liver disease(MAFLD)is a complex,heterogenous and progressive disease that is characterised by substantial phenotypic variability,which results in disparate clinical presentations and outcomes(1-4).Notably,only a proportion of patients with MAFLD progress to the more advanced stages of the disease.Therefore,the identification of the subgroups that have a high risk of disease progression is of paramount importance for clinical care,as well as drug development and clinical trials(5).展开更多
文摘Metabolic dysfunction-associated fatty liver disease(MAFLD)now affects roughly one-quarter of the world’s population,reflecting the global spread of obesity and insulin resistance.Reframing non-alcoholic fatty liver disease as MAFLD emphasizes its metabolic roots and spotlights the gut-liver axis,where intestinal dysbiosis acts as a key driver of hepatic injury.Altered microbial com-munities disrupt epithelial integrity,promote bacterial translocation,and trigger endotoxin-mediated inflammation that accelerates steatosis,lipotoxicity,and fibrogenesis.Concurrent shifts in bile acid signaling and short-chain fatty acid profiles further impair glucose and lipid homeostasis,amplifying cardiometabolic risk.Epidemiological studies reveal pervasive dysbiosis in MAFLD cohorts,linked to diet quality,sedentary behavior,adiposity,and host genetics.Newly developed microbiome-derived biomarkers,advanced elastography,and integrated multi-omics panels hold promise for non-invasive diagnosis and stratification,although external validation remains limited.In early trials,interventions that re-engineer the microbiota including tailored pre-/pro-/synbiotics,rational diet patterns,next-generation fecal microbiota transplantation,and bile-acid-modulating drugs show encouraging histological and metabolic gains.Optimal care will likely couple these tools with weight-centered lifestyle programmes in a pre-cision-medicine framework.Key challenges include inter-ethnic variability in microbiome signatures,the absence of consensus treatment algorithms,and regulatory barriers to live biotherapeutics.Rigorous longitudinal studies are required to translate mechanistic insight into durable clinical benefit and improve patient-centered outcome measures.
文摘Metabolic associated fatty liver disease(MAFLD),formerly named non-alcoholic fatty liver disease is the most common liver disorder in many countries.The inflammatory subtype termed steatohepatitis is a driver of disease progression to cirrhosis,hepatocellular carcinoma,liver transplantation,and death,but also to extrahepatic complications including cardiovascular disease,diabetes and chronic kidney disease.The plasticity of macrophages in response to various environmental cues and the fact that they can orchestrate cross talk between different cellular players during disease development and progression render them an ideal target for drug development.This report reviews recent advances in our understanding of macrophage biology during the entire spectrum of MAFLD including steatosis,inflammation,fibrosis,and hepatocellular carcinoma,as well as for the extra-hepatic manifestations of MAFLD.We discuss the underlying molecular mechanisms of macrophage activation and polarization as well as cross talk with other cell types such as hepatocytes,hepatic stellate cells,and adipose tissue.We conclude with a discussion on the potential translational implications and challenges for macrophage based therapeutics for MAFLD.
基金Supported by A National Health and Medical Research Council Project grant, APP1006759the Robert W. Storr bequest to the Sydney Medical Foundation of the University of Sydney, to Ahlenstiel G and George J+1 种基金an International Postgraduate Research Scholarshipsan Australian Postgraduate Award of the University of Sydney, to Eslam M
文摘Metabolic changes are inextricably linked to chronic hepatitis C(CHC).Recently polymorphisms in the IFNL3(IL28B)region have been shown to be strongly associated with spontaneous and treatment induced recovery from hepatitis C virus(HCV)infection.Further,circumstantial evidence suggests a link between IFNL3single nucleotide polymorphisms and lipid metabolism,steatosis and insulin resistance in CHC.The emerging picture suggests that the responder genotypes of IFNL3polymorphisms are associated with a higher serum lipid profile,and less frequent steatosis and insulin resistance.This review analyzes the current data regarding this interaction and its meaning for HCV pathogenesis and disease progression.
基金funded by grants from the National Natural Science Foundation of China(82070588,82370577)High Level Creative Talents from Department of Public Health in Zhejiang Province(S2032102600032)+7 种基金National Key R&D Program of China(2023YFA1800801)supported in part by grants from the School of Medicine,University of Verona,Verona,Italysupported in part by the Southampton National Institute for Health and Care Research(NIHR)Biomedical Research Centre(NIHR203319)supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydneya National Health and Medical Research Council of Australia(NHMRC)Program Grant(APP1053206)Investigator and MRFF grants(APP2032407,NCRI000183,APP2016215,APP 2010795APP1196492)a Cancer Institute,NSW grant(2021/ATRG2028).
文摘Background and Objective:Obesity is a global health issue closely linked to multiple cardiovascular and metabolic conditions.The renaming of nonalcoholic fatty liver disease(NAFLD)to metabolic dysfunction-associated fatty liver disease(MAFLD)has sparked discussions about renaming nonalcoholic fatty pancreas disease(NAFPD).This narrative review explores the potential benefits and challenges of renaming NAFPD to metabolic dysfunction-associated fatty pancreas disease(MAFPD)and its potential clinical implications.Methods:The review employs a narrative approach,synthesizing existing literature and expert opinions to evaluate the rationale behind and the possible implications of renaming NAFPD to MAFPD.Key Content and Findings:NAFPD is increasingly recognized worldwide but lacks standardized diagnostic criteria,hindering its independent classification as a disease.Renaming NAFPD to MAFPD may enhance diagnostic accuracy,prognostic prediction,and personalized treatment strategies.It may also facilitate global epidemiological research,data sharing,and collaboration.Major challenges include establishing uniform diagnostic guidelines for promoting and educating about the newly proposed terminology.Conclusions:The proposed renaming from NAFPD to MAFPD may offer promising benefits despite challenges.It may also lead to improved management and understanding of the disease,potentially benefiting global healthcare strategies aimed at addressing obesity-related pancreatic complications.
基金supported by a National Health and Medical Research Council of Australia(NHMRC)investigator and ideas grants[AAP2008983 and APP2001692].
文摘Metabolic dysfunction-associated fatty liver disease(MAFLD)has become the leading cause of chronic liver disease worldwide,with fibrosis recognized as the main prognostic factor and therapeutic target.While early-stage fibrosis is reversible,advanced fibrosis poses a significant clinical challenge due to limited treatment options,highlighting the need for innovative management strategies.Recent studies have shown that alternative pre-mRNA splicing,a critical mechanism regulating gene expression and protein diversity,plays a fundamental role in the pathogenesis of MAFLD and associated fibrosis.Understanding the complex relationship between alternative splicing and fibrosis progression in MAFLD could pave the way for novel therapeutic approaches and improve clinical outcomes.In this review,we describe the intricate mechanisms of alternative splicing in fibrosis associated with MAFLD.Specifically,we explored the pivotal of splicing factors,and RNA-binding proteins,highlighting their critical interactions with metabolic and epigenetic regulators.Furthermore,we provide an overview of the latest advancements in splicing-based therapeutic strategies and biomarker development.Particular emphasis is placed on the potential application of antisense oligonucleotides for rectifying splicing anomalies,thereby laying the foundation for precision medicine approaches in the treatment of MAFLDassociated fibrosis.
基金the Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydneya National Health and Medical Research Council of Australia(NHMRC)Program Grant(No.APP1053206 and APP1149976)+2 种基金Project grants(No.APP1107178 and APP1108422)Ming-Hua Zheng is supported by grants from the National Natural Science Foundation of China(No.81500665)High Level Creative Talents from Department of Public Health in Zhejiang Province and Project of New Century 551 Talent Nurturing in Wenzhou.
文摘The term non-alcoholic fatty liver disease(NAFLD)was coined in 1980 to characterize a disease similar to alcoholic fatty liver disease that developed in patients without a history of excessive alcohol intake.[1]Morphologically,NAFLD is characterized by excess fatty infiltration of the liver in the absence of known causes of liver disease(eg,alcohol,autoimmune liver disease,viral hepatitis,etc).The clinical manifestations of NAFLD(both hepatic and extrahepatic)depend on the outcome of complex interactions between its primary drivers including poor lifestyle habits and diet,a dysfunctional microbiota,genetic predisposition,and environmental cues that result in metabolic dysfunction and liver disease.However,bringing all patients with their markedly different clinical courses under the NAFLD umbrella belies its complexity and implies a homogeneous disease state that then negatively impacts clinical management and a deeper understanding of pathogenesis.With advances in current knowledge on the spectrum of fatty liver diseases,it is apparent that the fourdecade-old outdated term NAFLD can no longer serve to usefully describe a highly heterogeneous disease.The disease as we understand it today not only impacts patients who consume alcohol and those who do not,but also potentially impacts all patients with any form of liver disease,by acting as a disease modifier.[2]
文摘Background:With the rising global prevalence of fatty liver disease related to metabolic dysfunction,the association of this common liver condition with chronic kidney disease(CKD)has become increasingly evident.In 2020,the more inclusive term metabolic dysfunction-associated fatty liver disease(MAFLD)was proposed to replace the term non-alcoholic fatty liver disease(NAFLD).The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD.However,to date,there is no appropriate guidance on CKD in individuals with MAFLD.Furthermore,there has been little attention paid to the link between MAFLD and CKD in the Nephrology community.Methods and Results:Using a Delphi-based approach,a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD.Conclusions:This Delphi-based consensus statement provided guidance on the epidemiology,mechanisms,management and treatment of MAFLD and CKD,as well as the relationship between the severity of MAFLD and risk of CKD,which establish a framework for the early prevention and management of these two common and interconnected diseases.
基金ME is supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydney,the National Health and Medical Research Council of Australia(NHMRC)program grants(1053206 and 1149976)various project grants(1107178,1108422,and 2001692).
文摘The prevalence of metabolic(dysfunction)-associated fatty liver disease(MAFLD)is rapidly increasing and affects up to two billion individuals globally,and this has also resulted in increased risks for cirrhosis,hepatocellular carcinoma,and liver transplants.In addition,it has also been linked to extrahepatic consequences,such as cardiovascular disease,diabetes,and various types of cancers.However,only a small proportion of patients with MAFLD develop these complications.Therefore,the identification of high-risk patients is paramount.Liver fibrosis is the major determinant in developing these complications.Although,liver biopsy is still considered the gold standard for the assessment of patients with MAFLD.Because of its invasive nature,among many other limitations,the search for noninvasive biomarkers for MAFLD remains an area of intensive research.In this review,we provide an update on the current and future biomarkers of MAFLD,including a discussion of the associated genetics,epigenetics,microbiota,and metabolomics.We also touch on the next wave of multiomic-based biomarkers.
基金ME and JG are supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydneya National Health and Medical Research Council of Australia(NHMRC)Program Grant(APP1053206,APP1149976)+3 种基金Project grants(APP1107178 and APP1108422)MHZ is supported by grants from the National Natural Science Foundation of China(82070588)High Level Creative Talents from Department of Public Health in Zhejiang Province(S2032102600032)Project of New Century 551 Talent Nurturing in Wenzhou.
文摘Metabolic-associated fatty liver disease(MAFLD)(1),formerly known as non-alcoholic fatty liver disease,is a major causes of liver cirrhosis(2).MAFLD represents a growing global health and economic burden since approximately one in four people have the disease(3).As a consequence,MAFLD-related cirrhosis is expected to become the leading cause for liver failure and liver cancer,and the major indication for liver transplantation this century(3).
基金This work was supported by grants from the National Natural Science Foundation of China(82070588)High Level Creative Talents from Department of Public Health in Zhejiang Province(S2032102600032)+3 种基金Project of New Century 551 Talent Nurturing in Wenzhou.GT was supported in part by grants from the University School of Medicine of Verona(Verona,Italy)CDB was supported in part by the Southampton NIHR Biomedical Research Centre(ISBRC-20004)UK.ME and JG were supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydney(Sydney,Australia)and the National Health and Medical Research Council of Australia(NHMRC)Program(APP1053206,APP1149976)Project(APP1107178 and APP1108422)grants.
文摘Background and Aims:In Europeans,variants in the hydroxysteroid 17-beta dehydrogenase 13(HSD17B13)gene impact liver histology in metabolic-associated fatty liver disease(MAFLD).The impact of these variants in ethnic Chinese is unknown.The aim of this study was to investigate the potential associations in Chinese patients.Methods:In total,427 Han Chinese with biopsy-confirmed MAFLD were enrolled.Two single nucleotide polymorphisms in HSD17B13 were genotyped:rs72613567 and rs6531975.Logistic regression was used to test the association between the single nucleotide polymorphisms and liver histology.Results:In our cohort,the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis[odds ratio(OR):2.93(1.20–7.17),p=0.019 for the additive model;OR:3.32(1.39–7.91),p=0.007 for the recessive model],representing an inverse association as compared to the results from European cohorts.In contrast,we observed a protective effect on fibrosis for the minor A allele carriers of the HSD17B13 rs6531975 variant[OR:0.48(0.24–0.98),p=0.043 for the additive model;OR:0.62(0.40–0.94),p=0.025 for the dominant model].HSD17B13 variants were only associated with fibrosis but no other histological features.Furthermore,HSD17B13 rs6531975 modulated the effect of PNPLA3 rs738409 on hepatic steatosis.Conclusions:HSD17B13 rs72613567 is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans.These data exemplify the need for studying diverse populations in genetic studies in order to fine map genome-wide association studies signals.
文摘The majority of global deaths are attributed to one of the noncommunicable diseases(NCDs),and cancer is projected to be the leading cause of death worldwide in the 21st century(1).There were 18.1 million incident cancer cases worldwide in 2018,43.8 million are living with cancer and 9.6 million deaths from cancer.One in 6 deaths is due to cancer and these numbers are projected to rise to 13 million by 2030,more than that from tuberculosis,malaria and HIV/AIDS combined.In addition,the total annual global cost of cancer was estimated at around US$1.16 trillion,representing a significant burden on health care systems and families(1).
基金Mohammed Eslam is supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of SydneyNational Health and Medical Research Council of Australia(NHMRC)Program Grants(1053206 and 1149976)Project grants(1107178 and 1108422,2001692).
文摘Metabolic(dysfunction)-associated fatty liver disease(MAFLD;formerly known as non-alcoholic fatty liver disease)is the most common liver disorder,affecting around one-third of the population worldwide(1).MAFLD is a heterogeneous disease with a spectrum of liver pathologies that spans from hepatic lipid accumulation(steatosis)to chronic inflammation(steatohepatitis),which can progress to cirrhosis and hepatocellular carcinoma.It is impacted by a myriad of factors,including metabolic health,biological and chronological age,genetics and epigenetics(2-4).However,only a proportion(5-40%)of patients develop liver inflammation or steatohepatitis(5).This transition is a cardinal feature of progressive liver disease,which is the precursor to the development of the hepatic and extra-hepatic outcomes.
基金ME is supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of SydneyNational Health and Medical Research Council of Australia(NHMRC)Program Grants(1053206 and 1149976)Project grants(1107178 and 1108422,2001692).
文摘With the widespread increase in energy intake and physical inactivity,the prevalence of metabolic health is declining.Consequently,metabolic associated fatty liver disease(MAFLD)[formerly known as non-alcoholic fatty liver disease(NAFLD)]has risen in prevalence and present a significant challenge to global health causing considerable morbidity and mortality,particularly when fibrosis is present(1).
基金National Health and Medical Research Council of Australia(NHMRC)Program and Investigator Grants(2008983,1053206,and 1149976,to M.E.)Project and Ideas Grants(1107178 and 1108422,2001692,to M.E.).
文摘Background and Objective:Hepatocellular carcinoma(HCC)poses a significant global health burden and ranks as the fifth most prevalent cancer on a global scale.Hepatitis C virus(HCV)infection remains one of the major risk factors for HCC development.HCC is a heterogeneous disease,and the development of HCC caused by HCV is intricate and involves various factors,including genetic susceptibility,viral factors,immune response due to chronic inflammation,alcohol abuse,and metabolic dysfunction associated with fatty liver disease.In this review,we provide a comprehensive and updated review of research on the genetics and epigenetic mechanisms implicated in developing HCC associated with HCV infection.We also discuss the potential translational implications,including novel biomarkers and drugs for treatment.Methods:A comprehensive literature search was conducted in June 2023 in PubMed and Embase databases.Key Content and Findings:Recent findings indicate that a variety of genetic and epigenetic processes are involved in the pathogenesis and continue to exist even after the complete elimination of HCV.The deregulation of the epigenome has been identified as a significant factor in the deletrious effects of liver disease,especially during the initial stages when genetic alterations are uncommon.The enduring“epigenetic memory”of gene expression is believed to be regulated by epigenetic mechanisms,indicating that alterations caused by HCV infection continue to exist and are linked to the risk of development of liver cancer even after successful treatment.Systems biology analytical methods will be required to delineate the magnitude and significance of both genetic and epigenomic alterations in tumor evolution.Conclusions:By facilitating a more profound understanding of these aspects,this will ultimately foster the advancement of novel therapies and ultimately improve outcomes for patients.
基金supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydneya National Health and Medical Research Council of Australia(NHMRC)Program and investigator grants(APP2008983 and APP1053206)project and idea grants(APP2001692,APP1107178 and APP1108422).
文摘To provide clarity for research studies and clinical care,a set of positive criteria for adults and children with metabolic(dysfunction)associated fatty liver disease(MAFLD)was recently published and has subsequently been widely endorsed.The development and subsequent validation of the criteria for MAFLD has created a positive momentum for change.During the course of the ongoing discussion on the redefinition,some concerns have surfaced that we thought needs clarification.In this review,we provide a perspective on MAFLD and bringing clarity to some of the key aspects that have been recently raised.
文摘As of today,March 30,2020,when this Editorial is being written,the severe acute respiratory syndrome coronavirus-2(SARS-CoV-2),causal agent of the coronavirus disease(COVID-19)has been confirmed in more than 745,000 cases worldwide and has claimed the lives of more than 35,000 people.1 In addition to the morbidity and mortality associated with COVID-19,this betacoronavirus has placed several of the world's major economies in strife,mainly in Western Europe and North America,paralyzing travel and regular social interactions,making COVID-19 undoubtedly one of the most important pandemics in human history.
基金supported by the National Health and Medical Research Council of Australia(NHMRC)Program and Investigator Grants(Nos.2008983,1053206,and 1149976)Project and Ideas Grants(Nos.1107178,1108422,and 2001692).
文摘Metabolic dysfunction-associated fatty liver disease(MAFLD)is a complex,heterogenous and progressive disease that is characterised by substantial phenotypic variability,which results in disparate clinical presentations and outcomes(1-4).Notably,only a proportion of patients with MAFLD progress to the more advanced stages of the disease.Therefore,the identification of the subgroups that have a high risk of disease progression is of paramount importance for clinical care,as well as drug development and clinical trials(5).
