Study: Hepatic PTPRD Expression Impaired in Etiologies of Chronic Liver Disease Associated With Metabolic Disease

Data published in eGastroenterology highlight an important regulatory role of the hepatic protein tyrosine phosphatase delta (PTPRD)-STAT3 axis when maintaining glucose/lipid homeostasis, which is recapitulated in clinical manifestations of metabolic liver disease. The authors emphasize that strategies aimed at rescuing PTPRD function in diseased livers can represent novel therapeutic approaches in the elimination of underlying liver disease etiology, therefore restoring metabolic liver homeostasis.

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In patients with chronic hepatitis C virus infection, impaired hepatic expression of PTPRD is associated with increased STAT3 transcriptional activity and reduced survival in hepatocellular carcinoma. Despite the PTPRD-expressing hepatic cell types, signaling pathways within the liver microenvironment that are responsive to PTPRD and their role in nonviral liver disease are largely unknown, wrote the study authors. For this reason, the investigators conducted a study to assess PTPRD expression in single-cell and bulk liver transcriptomic data from mice and humans, establishing a Ptprd-deficient mouse model for metabolic dysfunction-associated steatohepatitis (MASH). Additionally, the authors noted that their findings provide information on the role of PTPRD in the regulation of multiple aspects of liver metabolism, such as glucose/lipid homeostasis and clinical manifestations of metabolic disease.

The analysis was restricted to wild-type (Ptprd+/+) and Ptprd heterozygous (Ptprd+/−) mice, according to the investigators. Ptprd+/+ (n = 22) and Ptprd+/− (n = 13) male mice aged 8 weeks received a single intraperitoneal injection of diethylnitrosamine (100 mg/kg) and were subsequently fed with a choline-deficient, L-amino acid-defined, high-fat diet (CDA-HFD) for 16 weeks. Additionally, glucose levels were determined in blood collected from the tail vein using a handheld Accu-Chek active glucometer (Roche) after overnight fasting.

The analysis of individuals ranked according to PTPRD expression and Ptprd-deficient mice indicated that PTPRD levels were associated with hepatic glucose and lipid signaling and peroxisome function. Additionally, hepatic PTPRD expression was found to be impaired in etiologies of chronic liver diseases that are associated with metabolic disease. The investigators further validated PTPRD as a STAT3 phosphatase in the liver, acting as a regulator of peroxisomal fatty acid metabolism. In MASH, low PTPRD led to an increased liver steatosis in Ptprd+/− mice as well as a pronounced unfolded protein response, which then impacted insulin signaling. Therefore, this silencing of PTPRD blunted insulin-induced AKT phosphorylation. Subjects with obesity and low hepatic PTPRD expression exhibit an increase in levels of metabolic risk factors.

The investigators noted that the data highlighted an important regulatory role of hepatic PTPRD in maintaining hepatic lipid and glucose homeostasis as well as how its impaired expression is associated with the clinical manifestations of metabolic disease. Therapeutic strategies that either rescued PTPRD function or targeted PTPRD-sensitive signaling pathways will therefore represent interesting options to accompany measures aiming to eliminate the underlying liver disease etiology and restore metabolic liver homeostasis.

A limitation of the study was the use of a CDA-HFD model, according to the authors, because it is well-established to induce a MASH-like phenotype and not optimal to study glucose metabolism and diabetes. In addition, future validation using a conventional high-fat diet model, potentially combined with a liver-specific knockout and/or overexpression of Ptprd, could further strengthen the findings and validate its regulatory role, according to the investigators. The analysis of single-cell transcriptomic data suggested that PTPRD is expressed primarily in the epithelial compartment; however, additional research is needed to validate the hepatic cellular distribution of PTPRD protein expression.

The potential of PTPRD as an acknowledged minimally invasive biomarker remains to be evaluated, noted the authors, because they did not assess whether potentially shed components of the membrane protein PTPRD are secreted into the blood and associated with chronic liver disease. They emphasized that these points would need to be addressed in dedicated follow-up studies.

REFERENCE

Suarez AAR, Jühling F, Moehlin J, et al. Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease: eGastroenterology. 2025;3:e100159. doi:10.1136/egastro-2024-100159