Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease

蛋白质酪氨酸磷酸酶 磷酸酶 抑制器 蛋白磷酸酶2 酪氨酸 DUSP6型 疾病 生物化学 化学 磷酸化 医学 内科学 基因
作者
Armando Andres Roca Suarez,Frank Jühling,Julien Moehlin,Laurent Mailly,Alessia Virzì,Nicolas Brignon,Sarah Durand,Marine Oudot,Eugénie Schaeffer,Romain Martin,Laura Heydmann,C Bach,Zakaria Boulahtouf,Lea Girard,Emma Osswald,Carole Jamey,Daniel Brumaru,Nassim Dali‐Youcef,Atish Mukherji,Maria Saez-Palma,Barbara Testoni,Fabien Zoulim,Bhuvaneswari Koneru,Naoto Fujiwara,Yujin Hoshida,Emanuele Felli,Patrick Pessaux,Michel L. Tremblay,Romain Parent,Catherine Schuster,Thomas F. Baumert,Joachim Lupberger
标识
DOI:10.1136/egastro-2024-100159
摘要

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.
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