BACKGROUND The progression of non-alcoholic fatty liver disease(NAFLD)to non-alcoholic steatohepatitis(NASH)and liver fibrosis remains poorly understood,though liver sinusoidal endothelial cells(LSECs)are thought to p...BACKGROUND The progression of non-alcoholic fatty liver disease(NAFLD)to non-alcoholic steatohepatitis(NASH)and liver fibrosis remains poorly understood,though liver sinusoidal endothelial cells(LSECs)are thought to play a central role in disease pathogenesis.AIM To investigate the role of TSC22D1 in NAFLD fibrosis through its regulation of LSEC dysfunction and macrophage polarization.METHODS We analysed single-cell transcriptomic data(GSE129516)from NASH and normal INTRODUCTION Non-alcoholic fatty liver disease(NAFLD)is a global health issue associated with increasing rates of obesity and metabolic syndrome.NAFLD encompasses a spectrum of conditions,ranging from simple steatosis to more severe manifestations such as non-alcoholic steatohepatitis(NASH),fibrosis,cirrhosis,and hepatocellular carcinoma.Liver fibrosis represents a critical stage in NAFLD progression because of its strong association with impaired liver function,progression to end-stage liver disease,and increased disease-related mortality[1].The pathogenesis of NAFLD is multifactorial and involves complex interactions between genetic predispositions,insulin resistance,dietary factors,and chronic inflammation[2].Liver sinusoidal endothelial cells(LSECs),which are highly specialized endothelial cells lining the hepatic sinusoids,critically contribute to both the pathogenesis and progression of NAFLD[3,4].In NAFLD,LSECs undergo structural alterations such as reduced fenestrations,which impair hepatic microcirculation and hinder the exchange of lipids and other substances,thereby promoting lipid accumulation in hepatocytes[5].Furthermore,dysfunctional LSECs exacerbate hepatic inflammation and fibrogenesis by releasing pro-inflammatory cytokines and fibrogenic mediators,such as transforming growth factor-β(TGF-β).These factors activate hepatic stellate cells(HSCs),resulting in the pathological accumulation of extracellular matrix components[6].LSECs are also highly susceptible to oxidative stress,further aggravating hepatic injury[7,8].Importantly,LSECs influence macrophage polarization by producing chemotactic and immunomodulatory factors,thereby promoting the recruitment and activation of M1-type pro-inflammatory CONCLUSION In conclusion,this study provides a comprehensive understanding of the role of TSC22D1 in the pathogenesis of NAFLD fibrosis.We elucidated the mechanisms through which TSC22D1 drives LSEC microvascularization and EndMT,as well as its role in promoting the secretion of TWEAK,which induces macrophage polarization towards the M1 phenotype.These findings offer novel insights into the pathophysiology of NAFLD,particularly the interplay between endothelial dysfunction,inflammation,and fibrosis.Importantly,our results highlight the potential of TSC22D1 as a therapeutic target for NAFLD.Future research should focus on validating these mechanisms in human clinical cohorts and deve-loping targeted interventions,such as TSC22D1 inhibitors or modulators of the TWEAK/FN14 signalling pathway,to translate these findings into effective treatments for NAFLD progression to fibrosis.展开更多
基金Supported by the Changzhou Science and Techology Program,No.CJ20241048Changzhou High-Level Medical Talents Training Project,No.2022CZBJ105+1 种基金Development Foundation of the Affiliated Hospital of Xuzhou Medical University,No.XYFC202304 and No.XYFM202307The Open Project of Jiangsu Provincial Key Laboratory of Laboratory Medicine,No.JSKLM-Z-2024-002.
文摘BACKGROUND The progression of non-alcoholic fatty liver disease(NAFLD)to non-alcoholic steatohepatitis(NASH)and liver fibrosis remains poorly understood,though liver sinusoidal endothelial cells(LSECs)are thought to play a central role in disease pathogenesis.AIM To investigate the role of TSC22D1 in NAFLD fibrosis through its regulation of LSEC dysfunction and macrophage polarization.METHODS We analysed single-cell transcriptomic data(GSE129516)from NASH and normal INTRODUCTION Non-alcoholic fatty liver disease(NAFLD)is a global health issue associated with increasing rates of obesity and metabolic syndrome.NAFLD encompasses a spectrum of conditions,ranging from simple steatosis to more severe manifestations such as non-alcoholic steatohepatitis(NASH),fibrosis,cirrhosis,and hepatocellular carcinoma.Liver fibrosis represents a critical stage in NAFLD progression because of its strong association with impaired liver function,progression to end-stage liver disease,and increased disease-related mortality[1].The pathogenesis of NAFLD is multifactorial and involves complex interactions between genetic predispositions,insulin resistance,dietary factors,and chronic inflammation[2].Liver sinusoidal endothelial cells(LSECs),which are highly specialized endothelial cells lining the hepatic sinusoids,critically contribute to both the pathogenesis and progression of NAFLD[3,4].In NAFLD,LSECs undergo structural alterations such as reduced fenestrations,which impair hepatic microcirculation and hinder the exchange of lipids and other substances,thereby promoting lipid accumulation in hepatocytes[5].Furthermore,dysfunctional LSECs exacerbate hepatic inflammation and fibrogenesis by releasing pro-inflammatory cytokines and fibrogenic mediators,such as transforming growth factor-β(TGF-β).These factors activate hepatic stellate cells(HSCs),resulting in the pathological accumulation of extracellular matrix components[6].LSECs are also highly susceptible to oxidative stress,further aggravating hepatic injury[7,8].Importantly,LSECs influence macrophage polarization by producing chemotactic and immunomodulatory factors,thereby promoting the recruitment and activation of M1-type pro-inflammatory CONCLUSION In conclusion,this study provides a comprehensive understanding of the role of TSC22D1 in the pathogenesis of NAFLD fibrosis.We elucidated the mechanisms through which TSC22D1 drives LSEC microvascularization and EndMT,as well as its role in promoting the secretion of TWEAK,which induces macrophage polarization towards the M1 phenotype.These findings offer novel insights into the pathophysiology of NAFLD,particularly the interplay between endothelial dysfunction,inflammation,and fibrosis.Importantly,our results highlight the potential of TSC22D1 as a therapeutic target for NAFLD.Future research should focus on validating these mechanisms in human clinical cohorts and deve-loping targeted interventions,such as TSC22D1 inhibitors or modulators of the TWEAK/FN14 signalling pathway,to translate these findings into effective treatments for NAFLD progression to fibrosis.
