Hepatocyte-derived DPP4 regulates portal GLP-1 bioactivity, glucose production and its absence alters liver disease progression (F480+ CELLS)

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 and F4/80+ cells were isolated using the liver dissociation kit from Miltenyi Biotech. Total RNA was isolated using Trizol as permanufacturer's protocol, and processed for NanoString analysis using manufacturer's protocol, lastly analyzed using nSolver