Armando Andres Roca Suarez, Frank Jühling, Julien Moehlin, Laurent Mailly, Alessia Virzì, Nicolas Brignon, Sarah C Durand, Marine A Oudot, Eugenie Schaeffer, Romain Martin, Laura Meiss-Heydmann, Charlotte 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
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引用次数: 0
Abstract
Abstract:
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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