Objective Impaired hepatic expression of protein tyrosine phosphatase delta(PTPRD)is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic...Objective Impaired hepatic expression of protein tyrosine phosphatase delta(PTPRD)is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection.However,the PTPRD-expressing hepatic cell types,signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.Methods We studied PTPRD expression in single-cell and bulk liver transcriptomic data from mice and humans,and established a Ptprd-deficient mouse model for metabolic dysfunction-associated steatohepatitis(MASH).Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays.The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to PTPRD expression and analysing its association with metabolic disease markers.Results The analysis of individuals ranked according to PTPRD expression and Ptprd-deficient mice,showed that PTPRD levels were associated with hepatic glucose/lipid signalling and peroxisome function.Hepatic PTPRD expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease.We further validated PTPRD as a STAT3 phosphatase in the liver,acting as a regulator of peroxisomal fatty acid metabolism.During MASH,low PTPRD led to increased liver steatosis in Ptprd+/−mice and a pronounced unfolded protein response,which impacts insulin signalling.Accordingly,silencing of PTPRD blunted insulin-induced AKT phosphorylation.Patients with obesity and low hepatic PTPRD expression exhibit increased levels of metabolic risk factors.Conclusion Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis,which is recapitulated in clinical manifestations of metabolic liver disease.展开更多
Chronic hepatitis B is the leading cause of hepatocellular carcinoma and a significant global health issue,affecting over 296 million people worldwide,with 15 million people coinfected with hepatitis delta virus(HDV)s...Chronic hepatitis B is the leading cause of hepatocellular carcinoma and a significant global health issue,affecting over 296 million people worldwide,with 15 million people coinfected with hepatitis delta virus(HDV)suffering accelerated disease progression.Recent advances in single-cell sequencing and spatial transcriptomics offer promising insights to improve the understanding of the liver’s immune responses and hepatitis B virus(HBV)-infected cell distribution,with the final goal being the achievement of an HBV‘functional cure’.In this issue of eGastroenterology,Cross et al used the GeoMx nanostring digital spatial profiling(DSP)technology to study gene expression in the liver tissues of three patients(one HBV-monoinfected,one HBV/HDV coinfected and one HBV/human immunodeficiency virus(HIV)coinfected).Unlike other spatial transcriptomics techniques,GeoMx DSP allows targeted selection of specific tissue regions(regions of interest)for analysis,enabling precise gene expression mapping.The study revealed spatially distinct transcriptomic signatures related to immune features and viral burden,identifying a component of underinvestigated immune cells.Despite the small sample size,this proof-of-concept study demonstrates the feasibility of spatial transcriptomics in analysing HBV infections.Future advances,such as integrating viral proteins and nucleic acids,will enhance the understanding of spatial viral replication.Challenges in tissue processing,data analysis and costs remain before spatial transcriptomics can be applied as a diagnostic tool,but ongoing multiomics approaches offer promise for improved diagnosis and therapy.展开更多
基金supported by the European Union(ERC-AdG-2014 HEPCIR ERC POC PRELICAN 755460,ERC POC HEPCAN 862551 to TFB,EU H2020 HEPCAR 667273 to TFB and JL,HORIZON-HLTH-2021-DISEASE-04-07 D-SOLVE#101057917 to TFB and JL,IP-cure-B project#847939 to FZ,ERC-AdG-2020-101021417 to YH)the French Cancer Agency(TheraHCC2.0 IHU201901299 to TFB)+9 种基金the Agence Nationale de la Recherche(ANR-21-RHUS-001 to TFB)the ANRS Maladies infectieusesémergentes(ANRS-MIE)(ECTZ103701,ECTZ131760,ECTZ160436,ECTZ171594 to JL,ECTZ104017 and ECTZ75178 to TFB,ECTZ4446 and ECTZ206376 to AARS)the Fondation de l’Universitéde Strasbourg(HEPKIN)(TBA-DON-0002),SATT Conectus,University of Strasbourg(CANCLAU)(TFB)the Inserm Plan Cancer 2019-2023the US National Institutes of Health(CA233794,CA255621,CA282178,CA288375 and CA283935 to YH)the Cancer Prevention and Research Institute of Texas(RR180016,RP200554 to YH)The AEPIC animal facility platform is financially supported by the CoRTecS network of the University of StrasbourgThis work of the Interdisciplinary Thematic Institute IMCBio,as part of the ITI 2021-2028 programme of the University of Strasbourg,CNRS and Inserm,was supported by IdEx Unistra(ANR-10-IDEX-0002)SFRI-STRAT’US project(ANR 20-SFRI-0012)EUR IMCBio(ANR-17-EURE-0023)under the framework of the French Investments for the Future Programme,as well as state funds managed within the France 2030 programme(reference ANR-21-RHUS-0001).
文摘Objective Impaired hepatic expression of protein tyrosine phosphatase delta(PTPRD)is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection.However,the PTPRD-expressing hepatic cell types,signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.Methods We studied PTPRD expression in single-cell and bulk liver transcriptomic data from mice and humans,and established a Ptprd-deficient mouse model for metabolic dysfunction-associated steatohepatitis(MASH).Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays.The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to PTPRD expression and analysing its association with metabolic disease markers.Results The analysis of individuals ranked according to PTPRD expression and Ptprd-deficient mice,showed that PTPRD levels were associated with hepatic glucose/lipid signalling and peroxisome function.Hepatic PTPRD expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease.We further validated PTPRD as a STAT3 phosphatase in the liver,acting as a regulator of peroxisomal fatty acid metabolism.During MASH,low PTPRD led to increased liver steatosis in Ptprd+/−mice and a pronounced unfolded protein response,which impacts insulin signalling.Accordingly,silencing of PTPRD blunted insulin-induced AKT phosphorylation.Patients with obesity and low hepatic PTPRD expression exhibit increased levels of metabolic risk factors.Conclusion Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis,which is recapitulated in clinical manifestations of metabolic liver disease.
基金supported by grants provided by the'Agence Nationale pour la Recherche sur le SIDA et les hepatites virales et les maladies infectieuses emergentes'(ANRS|MIE)under grant agreements ECTZ143165 and ECTZ210845by the French National Agency for Research(ANR,grant IHU EVEREST:ANR-23-IAHU-0008)。
文摘Chronic hepatitis B is the leading cause of hepatocellular carcinoma and a significant global health issue,affecting over 296 million people worldwide,with 15 million people coinfected with hepatitis delta virus(HDV)suffering accelerated disease progression.Recent advances in single-cell sequencing and spatial transcriptomics offer promising insights to improve the understanding of the liver’s immune responses and hepatitis B virus(HBV)-infected cell distribution,with the final goal being the achievement of an HBV‘functional cure’.In this issue of eGastroenterology,Cross et al used the GeoMx nanostring digital spatial profiling(DSP)technology to study gene expression in the liver tissues of three patients(one HBV-monoinfected,one HBV/HDV coinfected and one HBV/human immunodeficiency virus(HIV)coinfected).Unlike other spatial transcriptomics techniques,GeoMx DSP allows targeted selection of specific tissue regions(regions of interest)for analysis,enabling precise gene expression mapping.The study revealed spatially distinct transcriptomic signatures related to immune features and viral burden,identifying a component of underinvestigated immune cells.Despite the small sample size,this proof-of-concept study demonstrates the feasibility of spatial transcriptomics in analysing HBV infections.Future advances,such as integrating viral proteins and nucleic acids,will enhance the understanding of spatial viral replication.Challenges in tissue processing,data analysis and costs remain before spatial transcriptomics can be applied as a diagnostic tool,but ongoing multiomics approaches offer promise for improved diagnosis and therapy.
