Background:Gluconeogenesis is a critical metabolic pathway for maintaining glucose homeostasis,and its dysregulation can lead to glycometabolic disorders.This study aimed to identify hub biomarkers of these disorders ...Background:Gluconeogenesis is a critical metabolic pathway for maintaining glucose homeostasis,and its dysregulation can lead to glycometabolic disorders.This study aimed to identify hub biomarkers of these disorders to provide a theoretical foundation for enhancing diagnosis and treatment.Methods:Gene expression profiles from liver tissues of three well-characterized gluconeogenesis mouse models were analyzed to identify commonly differentially expressed genes(DEGs).Weighted gene co-expression network analysis(WGCNA),machine learning techniques,and diagnostic tests on transcriptome data from publicly available datasets of type 2 diabetes mellitus(T2DM)patients were employed to assess the clinical relevance of these DEGs.Subsequently,we identified hub biomarkers associated with gluconeogenesis-related glycometabolic disorders,investigated potential correlations with immune cell types,and validated expression using quantitative polymerase chain reaction in the mouse models.Results:Only a few common DEGs were observed in gluconeogenesis-related glycometabolic disorders across different contributing factors.However,these DEGs were consistently associated with cytokine regulation and oxidative stress(OS).Enrichment analysis highlighted significant alterations in terms related to cytokines and OS.Importantly,osteomodulin(OMD),apolipoprotein A4(APOA4),and insulin like growth factor binding protein 6(IGFBP6)were identified with potential clinical significance in T2DM patients.These genes demonstrated robust diagnostic performance in T2DM cohorts and were positively correlated with resting dendritic cells.Conclusions:Gluconeogenesis-related glycometabolic disorders exhibit considerable heterogeneity,yet changes in cytokine regulation and OS are universally present.OMD,APOA4,and IGFBP6 may serve as hub biomarkers for gluconeogenesis-related glycometabolic disorders.展开更多
Nonalcoholic steatohepatitis(NASH)has emerged as the major cause of end-stage liver diseases.However,an incomplete understanding of its molecular mechanisms severely dampens the development of pharmacotherapies.In the...Nonalcoholic steatohepatitis(NASH)has emerged as the major cause of end-stage liver diseases.However,an incomplete understanding of its molecular mechanisms severely dampens the development of pharmacotherapies.In the present study,through systematic screening of genome-wide mRNA expression from three mouse models of hepatic inflammation and fibrosis,we identified IGF2BP2,an N6-methyladenosine modification reader,as a key regulator that promotes NASH progression in mice.Adenovirus or adeno-associated virus-mediated overexpression of IGF2BP2 could induce liver steatosis,inflammation,and fibrosis in mice,at least in part,by increasing Tab2 mRNA stability.Besides,hepatic overexpression of IGF2BP2 mimicked gene expression profiles and molecular pathways of human NASH livers.Of potential clinical significance,IGF2BP2 expression is significantly upregulated in the livers of NASH patients.Moreover,knockdown of IGF2BP2 substantially alleviated liver injury,inflammation,and fibrosis in diet-induced NASH mice.Taken together,our findings reveal an important role of IGF2BP2 in NASH,which may provide a new therapeutic target for the treatment of NASH.展开更多
Nonalcoholic steatohepatitis(NASH)has emerged as a major cause of liver failure and hepatocellular carcinoma.Investigation into the molecular mechanisms that underlie steatosis-to-NASH progression is key to understand...Nonalcoholic steatohepatitis(NASH)has emerged as a major cause of liver failure and hepatocellular carcinoma.Investigation into the molecular mechanisms that underlie steatosis-to-NASH progression is key to understanding the development of NASH pathophysiology.Here,we present comprehensive multi-omic profiles of preclinical animal models to identify genes,non-coding RNAs,proteins,and plasma metabolites involved in this progression.In particular,by transcriptomics analysis,we identified Growth Differentiation Factor 3(GDF3)as a candidate noninvasive biomarker in NASH.Plasma GDF3 levels are associated with hepatic pathological features in patients with NASH,and differences in these levels provide a high diagnostic accuracy of NASH diagnosis(AUROC=0.90;95%confidence interval:0.85−0.95)with a good sensitivity(90.7%)and specificity(86.4%).In addition,by developing integrated proteomic-metabolomic datasets and performing a subsequent pharmacological intervention in a mouse model of NASH,we show that ferroptosis may be a potential target to treat NASH.Moreover,by using competing endogenous RNAs network analysis,we found that several miRNAs,including miR-582-5p and miR-292a-3p,and lncRNAs,including XLOC-085738 and XLOC-041531,are associated with steatosis-to-NASH progression.Collectively,our data provide a valuable resource into the molecular characterization of NASH progression,leading to the novel insight that GDF3 may be a potential noninvasive diagnostic biomarker for NASH while further showing that ferroptosis is a therapeutic target for the disease.展开更多
基金funded by the Project of National Natural Science Foundation of China(Grant Number:81873646).
文摘Background:Gluconeogenesis is a critical metabolic pathway for maintaining glucose homeostasis,and its dysregulation can lead to glycometabolic disorders.This study aimed to identify hub biomarkers of these disorders to provide a theoretical foundation for enhancing diagnosis and treatment.Methods:Gene expression profiles from liver tissues of three well-characterized gluconeogenesis mouse models were analyzed to identify commonly differentially expressed genes(DEGs).Weighted gene co-expression network analysis(WGCNA),machine learning techniques,and diagnostic tests on transcriptome data from publicly available datasets of type 2 diabetes mellitus(T2DM)patients were employed to assess the clinical relevance of these DEGs.Subsequently,we identified hub biomarkers associated with gluconeogenesis-related glycometabolic disorders,investigated potential correlations with immune cell types,and validated expression using quantitative polymerase chain reaction in the mouse models.Results:Only a few common DEGs were observed in gluconeogenesis-related glycometabolic disorders across different contributing factors.However,these DEGs were consistently associated with cytokine regulation and oxidative stress(OS).Enrichment analysis highlighted significant alterations in terms related to cytokines and OS.Importantly,osteomodulin(OMD),apolipoprotein A4(APOA4),and insulin like growth factor binding protein 6(IGFBP6)were identified with potential clinical significance in T2DM patients.These genes demonstrated robust diagnostic performance in T2DM cohorts and were positively correlated with resting dendritic cells.Conclusions:Gluconeogenesis-related glycometabolic disorders exhibit considerable heterogeneity,yet changes in cytokine regulation and OS are universally present.OMD,APOA4,and IGFBP6 may serve as hub biomarkers for gluconeogenesis-related glycometabolic disorders.
基金This study was supported by the National Key Research and Development Program of China(2018YFA0800402)the Shanghai Outstanding Academic Leaders Projects(21XD1423400)+3 种基金the Basic Research of Science,and Technology Innovation Action Plan(21JC1401300)Shanghai Sailing Program by Shanghai Municipal Science and Technology Committee(22YF1432800)China Postdoctoral Science Foundation Funded Project(2021M702183)the Youth Cultivation Project of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital(ynqn202107).
文摘Nonalcoholic steatohepatitis(NASH)has emerged as the major cause of end-stage liver diseases.However,an incomplete understanding of its molecular mechanisms severely dampens the development of pharmacotherapies.In the present study,through systematic screening of genome-wide mRNA expression from three mouse models of hepatic inflammation and fibrosis,we identified IGF2BP2,an N6-methyladenosine modification reader,as a key regulator that promotes NASH progression in mice.Adenovirus or adeno-associated virus-mediated overexpression of IGF2BP2 could induce liver steatosis,inflammation,and fibrosis in mice,at least in part,by increasing Tab2 mRNA stability.Besides,hepatic overexpression of IGF2BP2 mimicked gene expression profiles and molecular pathways of human NASH livers.Of potential clinical significance,IGF2BP2 expression is significantly upregulated in the livers of NASH patients.Moreover,knockdown of IGF2BP2 substantially alleviated liver injury,inflammation,and fibrosis in diet-induced NASH mice.Taken together,our findings reveal an important role of IGF2BP2 in NASH,which may provide a new therapeutic target for the treatment of NASH.
基金This study was supported by the National Key Research and Development Program of China(2018YFA0800402)the National Natural Science Foundation of China(81974119,82070887 and 81900771)+2 种基金the Shanghai Outstanding Academic Leaders Projects and Basic Research of Science and Technology Innovation Action Plan by Shanghai Municipal Science and Technology Committee(21XD1423400 and 21JC1401300)Excellent Youth Cultivation Program of Shanghai Sixth People’s Hospital(ynjq202202)the Shenzhen Science and technology R&D Foundation(KCXFZ202002011010445).
文摘Nonalcoholic steatohepatitis(NASH)has emerged as a major cause of liver failure and hepatocellular carcinoma.Investigation into the molecular mechanisms that underlie steatosis-to-NASH progression is key to understanding the development of NASH pathophysiology.Here,we present comprehensive multi-omic profiles of preclinical animal models to identify genes,non-coding RNAs,proteins,and plasma metabolites involved in this progression.In particular,by transcriptomics analysis,we identified Growth Differentiation Factor 3(GDF3)as a candidate noninvasive biomarker in NASH.Plasma GDF3 levels are associated with hepatic pathological features in patients with NASH,and differences in these levels provide a high diagnostic accuracy of NASH diagnosis(AUROC=0.90;95%confidence interval:0.85−0.95)with a good sensitivity(90.7%)and specificity(86.4%).In addition,by developing integrated proteomic-metabolomic datasets and performing a subsequent pharmacological intervention in a mouse model of NASH,we show that ferroptosis may be a potential target to treat NASH.Moreover,by using competing endogenous RNAs network analysis,we found that several miRNAs,including miR-582-5p and miR-292a-3p,and lncRNAs,including XLOC-085738 and XLOC-041531,are associated with steatosis-to-NASH progression.Collectively,our data provide a valuable resource into the molecular characterization of NASH progression,leading to the novel insight that GDF3 may be a potential noninvasive diagnostic biomarker for NASH while further showing that ferroptosis is a therapeutic target for the disease.
