Impaired protein tyrosine phosphatase delta is a driver of hepatic metabolic syndrome

Background & Aims: The protein tyrosine phosphatase delta (PTPRD) is suppressed in several diseases including cancers and hepatitis C virus (HCV) infection. To identify hepatic pathways responsive to PTPRD function and their role in liver disease, we analyzed liver transcriptomic and clinical data from patients and established a Ptprd-deficient liver disease mouse model. Methods: Based on liver transcriptomic data, healthy patients were classified according to PTPRD expression and gene set enrichment analysis (GSEA) was performed to identify signaling pathways associated with low PTPRD expression. We established a liver disease mouse model combining impaired PTPRD expression (Ptprd+/-) and high-fat diet to assess its impact on liver transcriptomics and hepatic metabolism. Identified pathways were validated by perturbation studies in primary human hepatocytes. The clinical relevance was validated in a cohort of patients with fatty liver disease by ranking of individuals according to hepatic PTPRD expression prior analyzing the association with metabolic disease markers. Results: In healthy individuals and Ptprd+/- mice fed with normal diet, low PTPRD levels associated with a gene expression pattern involved in glucose/lipid metabolism in the liver. During diet-induced liver disease, low hepatic PTPRD led to increased blood glucose and hepatic lipid levels in the Ptprd+/- animals. Moreover, Ptprd+/- animals exhibited a pronounced unfolded protein response, which has a potential impact on hepatic insulin signaling. Indeed, silencing of PTPRD in PHH blunted the insulin-induced AKT phosphorylation. Accordingly, obese patients with low hepatic PTPRD expression exhibit increased levels of clinical markers associated with metabolic disease. Conclusion: Our data suggests an important regulatory role of hepatic PTPRD in maintaining glucose/lipid homeostasis and how its impaired expression is associated with clinical manifestations of metabolic disease.