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

Elevated circulating dipeptidyl-peptidase 4 (DPP4) is a biomarker for liver disease, but its involvement in gluconeogenesis and 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 Dpp4-/- mice 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. Aged mice were fed a HFHC diet for 6 months, liver tissue was collected. Total RNA was isolated using Trizol as permanufacturer's protocol, and processed for NanoString analysis using manufacturer's protocol, lastly analyzed using nSolver