Hepatocyte-derived DPP4 regulates portal GLP-1 bioactivity, glucose production, and its absence alters liver disease progression.

Abstract

Elevated circulating dipeptidyl-peptidase 4 is a biomarker for liver disease, but its involvement in gluconeogenesis and in metabolic-associated fatty liver disease (MAFLD) progression remains unclear. Here we identified that DPP4 in hepatocytes but not Tie2+ endothelial cells regulates the local bioactivity of incretin hormones and gluconeogenesis. However, the complete absence of DPP4 (Dpp4-/-) in aged mice with metabolic syndrome accelerates liver fibrosis without altering dyslipidemia and steatosis. Analysis of transcripts from the livers of whole body Dpp4-/- displayed enrichment for inflammasome, p53, and senescence programs compared to littermate controls. High-fat high-cholesterol (HFHC)-feeding decreased Dpp4 expression in F4/80+ cells, with only minor changes in immune signaling. Moreover, in a lean mouse model of severe non-alcoholic fatty liver disease (NAFLD), phosphatidylethanolamine N-methyltransferase (Pemt -/-) mice fed with HFHC diet, we observed a 4-fold increase in circulating DPP4, disassociating its release from obesity. Lastly, we evaluated DPP4 levels in patients with hepatitis C infection with dysglycemia (HOMA-IR > 2) who underwent direct antiviral treatment (with or without ribavirin). DPP4 protein levels decreased with viral clearance, and DPP4 activity levels were reduced at longer-term follow-up in ribavirin-treated patients, although metabolic factors did not improve. These data suggest elevations in DPP4 during HCV infection are not primarily regulated by metabolic disturbances.