Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease(MAFLD).However,there are few reported lipotoxicity inhibitors...Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease(MAFLD).However,there are few reported lipotoxicity inhibitors.Here,we identified a natural anti-lipotoxicity candidate,HN-001,from the marine fungus Aspergillus sp.C1.HN-001 dose-and time-dependently reversed palmitic acid(PA)-induced hepatocyte death.This protection was associated with IRE-1a-mediated XBP-1 splicing inhibition,which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation.Knockdown of XBP-1s attenuated lipotoxicity,but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes.Notably,the ER stress and lipotoxicity amelioration was associated with PLA2.Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity,reduced lysophosphatidylcholine(LPC)level,subsequently ameliorated lipotoxicity.In contrast,overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001.Additionally,HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway.In vivo,chronic administration of HN-001(i.p.)in mice alleviated all manifestations of MAFLD,including hepatic steatosis,liver injury,inflammation,and fibrogenesis.These effects were correlated with PLA2/IRE-1a/XBP-1s axis and JNK signaling suppression.These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity,and provide a natural structural basis for developing anti-MAFLD candidates.展开更多
Background and Aims:Metabolic dysfunction-associ-ated fatty liver disease(MAFLD)is a new concept,pro-posed in 2020;however,its applicability in Asia populations has yet to be evaluated.Therefore,we aimed to compare th...Background and Aims:Metabolic dysfunction-associ-ated fatty liver disease(MAFLD)is a new concept,pro-posed in 2020;however,its applicability in Asia populations has yet to be evaluated.Therefore,we aimed to compare the difference in epidemiological and clinical characteris-tics between MAFLD and non-alcoholic fatty liver disease(NAFLD)among Asian populations.Methods:Based on the Jinchang cohort,30,633 participants were collected.The prevalence and incidence of MAFLD and NAFLD were used to analyze the epidemic characteristics and its overlapping effects.In addition,the corresponding clinical character-istics of the two diagnostic criteria populations were com-pared.Results:The prevalence rates of MAFLD and NAFLD were 21.03%and 18.83%,respectively.After an average 2.28-year follow-up,the incidence densities of MAFLD and NAFLD were 41.58 per 1,000 person-years and 37.69 per 1,000 person-years,respectively.With the increase of baseline age,body mass index(BMI),and waist circumfer-ence(WC)levels,the prevalence and incidence of MAFLD and NAFLD were on the rise(all ptrend<0.05).Among the total patients diagnosed at baseline or follow-up,most pa-tients had both MAFLD and NAFLD,accounting for 78.84%and 82.88%,respectively.Compared with NAFLD,MAFLD patients had greater proportions of males and metabolic diseases(diabetes,dyslipidemia),and had higher BMI,WC,liver enzymes,blood glucose,and lipid levels in the base-line diagnosis patients(p<0.05).Additionally,lean MAFLD patients had higher metabolic disorders than lean NAFLD patients(p<0.05).Conclusions:Compared with NAFLD,the newly proposed definition of MAFLD is more practical and accurate,and it can help identify more fatty liver pa-tients with high-risk diseases.展开更多
Background and Aims:Metabolic associated fatty liver disease(MAFLD)is a serious condition,and a simple meth-od is needed for practitioners to identify patients with the disease and have a high risk of disease progress...Background and Aims:Metabolic associated fatty liver disease(MAFLD)is a serious condition,and a simple meth-od is needed for practitioners to identify patients with the disease and have a high risk of disease progression.Meth-ods:We developed and validated a nomogram for fatty liver disease and reclassified the risk factors for MAFLD.The development cohort had 335 patients who received bioel-ectrical impedance analysis and liver ultrasound attenua-tion measurements at Shenzhen People’s Hospital between September 2020 and June 2021.The validation cohort had 200 patients from other hospitals who received the same evaluation.A random forest procedure and binary logistic analysis were used to screen for risk factors,establish a fatty liver disease predictive model,and forecast the risk of MAFLD.The performance of the nomogram was evaluated by measurement of discrimination,calibration,and clinical usefulness.Results:The nomogram provided good predic-tions in a model that included body mass index(BMI)and waist circumference.The areas under the curve of the nom-ogram were 0.793 in the development cohort and 0.774 in the validation cohort.The nomogram performed well for calibration,category-free net reclassification improvement,and integrated discrimination improvement.Decision curve analysis indicated the nomogram performed better than BMI for predicting net outcome.Conclusions:The nomo-gram was an effective screening tool for fatty liver disease,and for those overweight individuals,may help physicians make appropriate decisions regarding treatment of MAFLD.展开更多
In recent years,with the increasing incidence of obesity and other metabolic diseases,the prevalence of non-alcoholic fatty liver disease(NAFLD)has increased and it has become a major health problem affecting more tha...In recent years,with the increasing incidence of obesity and other metabolic diseases,the prevalence of non-alcoholic fatty liver disease(NAFLD)has increased and it has become a major health problem affecting more than one quarter of the world’s population.Recently,experts reached a consensus that NAFLD does not reflect the current knowledge,and metabolic dysfunctionassociated fatty liver disease(MAFLD)was suggested as a more appropriate term.MAFLD is not just a simple renaming of NAFLD.The definition of MAFLD allows a patient to have dual(or more)etiologies for their liver disease,which will help to exclude more heterogeneous patients.In this review,we introduce the significant differences between the definitions of NAFLD and MAFLD.In addition,we also describe the advantages of the term MAFLD in the pathophysiology,therapy,and patient management.展开更多
Metabolic(dysfunction)-associated fatty liver disease(MAFLD)affects a third of the population and is a leading cause of liver-related death.Since no effective treatments exist,novel approaches to drug development are ...Metabolic(dysfunction)-associated fatty liver disease(MAFLD)affects a third of the population and is a leading cause of liver-related death.Since no effective treatments exist,novel approaches to drug development are required.Unfortunately,outdated terminology and definitions of the disease are hampering efforts to develop new drugs and treatments.An international consensus panel has put forth an influential proposal for the disease to be renamed from nonalcoholic fatty liver disease(NAFLD)to MAFLD,includ-ing a proposal for how the disease should be diagnosed.As allies with the many stakeholders in MAFLD care―including patients,patients’advocates,clinicians,researchers,nurse and allied health groups,regional societies,and others―we are aware of the negative consequences of the NAFLD term and definition.We share the sense of urgency for change and will act in new ways to achieve our goals.Although there is much work to be done to overcome clinical inertia and reverse worrisome recent trends,the MAFLD initiative provides a firm foundation to build on.It provides a roadmap for moving for-ward toward more efficient care and affordable,sustainable drug and device innovation in MAFLD care.We hope it will bring promising new opportunities for a brighter future for MAFLD care and improve care and outcomes for patients of one of the globe’s largest and costliest public health burdens.From this viewpoint,we have revisited this initiative through the perspectives of drug development and regulatory science.展开更多
Background:Metabolic dysfunction-associated fatty liver disease(MAFLD)is now the most prevalent chronic liver disease worldwide,with an increasing incidence rate.MAFLD is a heterogeneous disease that can have a low or...Background:Metabolic dysfunction-associated fatty liver disease(MAFLD)is now the most prevalent chronic liver disease worldwide,with an increasing incidence rate.MAFLD is a heterogeneous disease that can have a low or high-risk profile for developing severe liver disease in its natural course.Recent evidence has highlighted the critical role of RNA methylation modification in the pathogenesis of various liver diseases.However,it remains unclear whether the RNA N1-methyladenosine(m1A)modification of immune cells could potentially contribute to the pathogenesis and heterogeneity of MAFLD.Materials and methods:To address this issue,we conducted an integrated bioinformatics analysis of MAFLD bulk and single-cell RNA sequencing(scRNA-seq)data to pinpoint m1A regulators in the network.This was followed by a description of the immune landscape,pathway enrichment analysis,and molecular subtyping.Results:The expression patterns of m1A regulatory genes stratify MAFLD into two molecular subtypes,Cluster 1 and Cluster 2.These subtypes demonstrate different immune cell infiltration with distinct inflammation characteristics,which suggest different immune-inflammatory responses in the liver.Notably,Cluster 2 is associated with pro-inflammation and may be more likely to lead to progressive stages of MAFLD.Through intersection analysis of weighted gene co-expression network analysis(WGCNA)and m1A regulatory genes,three true hub genes(ALKBH1,YTHDC1,and YTHDF3)were identified,all of which were strongly correlated with infiltrating immune cells.The specific signaling pathways involved in the three core genes were derived from genomic variation analysis.Furthermore,scRNA-seq data from 33,168 cells from six liver samples identified 26 cell clusters and eight cell types,with endothelial cells,macrophages,and monocytes showing the most significant differences between MAFLD and normal controls.The cell-cell communication network between immune cells and nonparenchymal cells was extremely sophisticated and changed significantly in MAFLD.Conclusions:In summary,these findings demonstrate the involvement of m1A in MAFLD heterogeneity and emphasize the crucial role of m1A modulation of immune cells in regulating inflammation in MAFLD.These results may suggest potential therapeutic strategies for MAFLD.展开更多
Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease,defined by several phases,ranging from benign fat accumulation to non-alcoholic steatohepatitis(NASH),which can lead to liver cancer and...Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease,defined by several phases,ranging from benign fat accumulation to non-alcoholic steatohepatitis(NASH),which can lead to liver cancer and cirrhosis.Although NAFLD is a disease of disordered metabolism,it also involves several immune cell-mediated inflammatory processes,either promoting and/or suppressing hepatocyte inflammation through the secretion of pro-inflammatory and/or anti-inflammatory factors to influence the NAFLD process.However,the underlying disease mechanism and the role of immune cells in NAFLD are still under investigation,leaving many open-ended questions.In this review,we presented the recent concepts about the interplay of immune cells in the onset and pathogenesis of NAFLD.We also highlighted the specific non-immune cells exhibiting immunological properties of therapeutic significance in NAFLD.We hope that this review will help guide the development of future NAFLD therapeutics.展开更多
基金This study was supported by National Natural Science Foundation of China(82260674 to Yong Rao,82160653 to Ling Huang)Fundamental Research Funds for Hainan University(KYQD(ZR)-21114 to Yong Rao,KYQD(ZR)-21089 to Ling Huang,China)+2 种基金Hainan Provincial Natural Science Foundation of China(822MS054 to Yong Rao)Natural Science Foundation of Guangdong Province(2021A1515010488 to Yong Rao,China)Central Public-interest Scientific Institution Basal Research Fund for CATAS-ITBB(1630052022016,1630052019011,China).
文摘Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease(MAFLD).However,there are few reported lipotoxicity inhibitors.Here,we identified a natural anti-lipotoxicity candidate,HN-001,from the marine fungus Aspergillus sp.C1.HN-001 dose-and time-dependently reversed palmitic acid(PA)-induced hepatocyte death.This protection was associated with IRE-1a-mediated XBP-1 splicing inhibition,which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation.Knockdown of XBP-1s attenuated lipotoxicity,but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes.Notably,the ER stress and lipotoxicity amelioration was associated with PLA2.Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity,reduced lysophosphatidylcholine(LPC)level,subsequently ameliorated lipotoxicity.In contrast,overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001.Additionally,HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway.In vivo,chronic administration of HN-001(i.p.)in mice alleviated all manifestations of MAFLD,including hepatic steatosis,liver injury,inflammation,and fibrogenesis.These effects were correlated with PLA2/IRE-1a/XBP-1s axis and JNK signaling suppression.These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity,and provide a natural structural basis for developing anti-MAFLD candidates.
基金This study was supported by the National Natural Science Foundation of China(Grant Number:41705122).
文摘Background and Aims:Metabolic dysfunction-associ-ated fatty liver disease(MAFLD)is a new concept,pro-posed in 2020;however,its applicability in Asia populations has yet to be evaluated.Therefore,we aimed to compare the difference in epidemiological and clinical characteris-tics between MAFLD and non-alcoholic fatty liver disease(NAFLD)among Asian populations.Methods:Based on the Jinchang cohort,30,633 participants were collected.The prevalence and incidence of MAFLD and NAFLD were used to analyze the epidemic characteristics and its overlapping effects.In addition,the corresponding clinical character-istics of the two diagnostic criteria populations were com-pared.Results:The prevalence rates of MAFLD and NAFLD were 21.03%and 18.83%,respectively.After an average 2.28-year follow-up,the incidence densities of MAFLD and NAFLD were 41.58 per 1,000 person-years and 37.69 per 1,000 person-years,respectively.With the increase of baseline age,body mass index(BMI),and waist circumfer-ence(WC)levels,the prevalence and incidence of MAFLD and NAFLD were on the rise(all ptrend<0.05).Among the total patients diagnosed at baseline or follow-up,most pa-tients had both MAFLD and NAFLD,accounting for 78.84%and 82.88%,respectively.Compared with NAFLD,MAFLD patients had greater proportions of males and metabolic diseases(diabetes,dyslipidemia),and had higher BMI,WC,liver enzymes,blood glucose,and lipid levels in the base-line diagnosis patients(p<0.05).Additionally,lean MAFLD patients had higher metabolic disorders than lean NAFLD patients(p<0.05).Conclusions:Compared with NAFLD,the newly proposed definition of MAFLD is more practical and accurate,and it can help identify more fatty liver pa-tients with high-risk diseases.
基金Commission of Science and Technology of Shenzhen(GJHZ20200731095401004).
文摘Background and Aims:Metabolic associated fatty liver disease(MAFLD)is a serious condition,and a simple meth-od is needed for practitioners to identify patients with the disease and have a high risk of disease progression.Meth-ods:We developed and validated a nomogram for fatty liver disease and reclassified the risk factors for MAFLD.The development cohort had 335 patients who received bioel-ectrical impedance analysis and liver ultrasound attenua-tion measurements at Shenzhen People’s Hospital between September 2020 and June 2021.The validation cohort had 200 patients from other hospitals who received the same evaluation.A random forest procedure and binary logistic analysis were used to screen for risk factors,establish a fatty liver disease predictive model,and forecast the risk of MAFLD.The performance of the nomogram was evaluated by measurement of discrimination,calibration,and clinical usefulness.Results:The nomogram provided good predic-tions in a model that included body mass index(BMI)and waist circumference.The areas under the curve of the nom-ogram were 0.793 in the development cohort and 0.774 in the validation cohort.The nomogram performed well for calibration,category-free net reclassification improvement,and integrated discrimination improvement.Decision curve analysis indicated the nomogram performed better than BMI for predicting net outcome.Conclusions:The nomo-gram was an effective screening tool for fatty liver disease,and for those overweight individuals,may help physicians make appropriate decisions regarding treatment of MAFLD.
基金supported by the National Natural Science Fund(No.81970545,82170609)Natural Science Foundation of Shandong Province(Major Project)(No.ZR2020KH006)Ji’nan Science and Technology Development Project(No.2020190790).
文摘In recent years,with the increasing incidence of obesity and other metabolic diseases,the prevalence of non-alcoholic fatty liver disease(NAFLD)has increased and it has become a major health problem affecting more than one quarter of the world’s population.Recently,experts reached a consensus that NAFLD does not reflect the current knowledge,and metabolic dysfunctionassociated fatty liver disease(MAFLD)was suggested as a more appropriate term.MAFLD is not just a simple renaming of NAFLD.The definition of MAFLD allows a patient to have dual(or more)etiologies for their liver disease,which will help to exclude more heterogeneous patients.In this review,we introduce the significant differences between the definitions of NAFLD and MAFLD.In addition,we also describe the advantages of the term MAFLD in the pathophysiology,therapy,and patient management.
文摘Metabolic(dysfunction)-associated fatty liver disease(MAFLD)affects a third of the population and is a leading cause of liver-related death.Since no effective treatments exist,novel approaches to drug development are required.Unfortunately,outdated terminology and definitions of the disease are hampering efforts to develop new drugs and treatments.An international consensus panel has put forth an influential proposal for the disease to be renamed from nonalcoholic fatty liver disease(NAFLD)to MAFLD,includ-ing a proposal for how the disease should be diagnosed.As allies with the many stakeholders in MAFLD care―including patients,patients’advocates,clinicians,researchers,nurse and allied health groups,regional societies,and others―we are aware of the negative consequences of the NAFLD term and definition.We share the sense of urgency for change and will act in new ways to achieve our goals.Although there is much work to be done to overcome clinical inertia and reverse worrisome recent trends,the MAFLD initiative provides a firm foundation to build on.It provides a roadmap for moving for-ward toward more efficient care and affordable,sustainable drug and device innovation in MAFLD care.We hope it will bring promising new opportunities for a brighter future for MAFLD care and improve care and outcomes for patients of one of the globe’s largest and costliest public health burdens.From this viewpoint,we have revisited this initiative through the perspectives of drug development and regulatory science.
基金This work was funded by the National Natural Science Foundation of China(82000620,81870449)GuangDong Basic and Applied Basic Research Foundation(2023A1515010583)+1 种基金China Postdoctoral Science Foundation(2022M723610)Natural Science Foundation of Xinjiang Uyghur Autonomous Region(2020D01C006).
文摘Background:Metabolic dysfunction-associated fatty liver disease(MAFLD)is now the most prevalent chronic liver disease worldwide,with an increasing incidence rate.MAFLD is a heterogeneous disease that can have a low or high-risk profile for developing severe liver disease in its natural course.Recent evidence has highlighted the critical role of RNA methylation modification in the pathogenesis of various liver diseases.However,it remains unclear whether the RNA N1-methyladenosine(m1A)modification of immune cells could potentially contribute to the pathogenesis and heterogeneity of MAFLD.Materials and methods:To address this issue,we conducted an integrated bioinformatics analysis of MAFLD bulk and single-cell RNA sequencing(scRNA-seq)data to pinpoint m1A regulators in the network.This was followed by a description of the immune landscape,pathway enrichment analysis,and molecular subtyping.Results:The expression patterns of m1A regulatory genes stratify MAFLD into two molecular subtypes,Cluster 1 and Cluster 2.These subtypes demonstrate different immune cell infiltration with distinct inflammation characteristics,which suggest different immune-inflammatory responses in the liver.Notably,Cluster 2 is associated with pro-inflammation and may be more likely to lead to progressive stages of MAFLD.Through intersection analysis of weighted gene co-expression network analysis(WGCNA)and m1A regulatory genes,three true hub genes(ALKBH1,YTHDC1,and YTHDF3)were identified,all of which were strongly correlated with infiltrating immune cells.The specific signaling pathways involved in the three core genes were derived from genomic variation analysis.Furthermore,scRNA-seq data from 33,168 cells from six liver samples identified 26 cell clusters and eight cell types,with endothelial cells,macrophages,and monocytes showing the most significant differences between MAFLD and normal controls.The cell-cell communication network between immune cells and nonparenchymal cells was extremely sophisticated and changed significantly in MAFLD.Conclusions:In summary,these findings demonstrate the involvement of m1A in MAFLD heterogeneity and emphasize the crucial role of m1A modulation of immune cells in regulating inflammation in MAFLD.These results may suggest potential therapeutic strategies for MAFLD.
文摘Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease,defined by several phases,ranging from benign fat accumulation to non-alcoholic steatohepatitis(NASH),which can lead to liver cancer and cirrhosis.Although NAFLD is a disease of disordered metabolism,it also involves several immune cell-mediated inflammatory processes,either promoting and/or suppressing hepatocyte inflammation through the secretion of pro-inflammatory and/or anti-inflammatory factors to influence the NAFLD process.However,the underlying disease mechanism and the role of immune cells in NAFLD are still under investigation,leaving many open-ended questions.In this review,we presented the recent concepts about the interplay of immune cells in the onset and pathogenesis of NAFLD.We also highlighted the specific non-immune cells exhibiting immunological properties of therapeutic significance in NAFLD.We hope that this review will help guide the development of future NAFLD therapeutics.
