Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease

Baumeier, Christian; Schlüter, Luisa; Saussenthaler, Sophie; Laeger, Thomas; Rödiger, Maria; Alaze, Stella Amelie; Fritsche, Louise; Häring, Hans-Ulrich; Stefan, Norbert; Fritsche, Andreas; Schwenk, Robert Wolfgang; Schürmann, Annette

( Figure 2C ). As transmembrane bound DPP4 can be shed from hepatocytes [23] , we studied the capacity of DPP4 release by analyzing plasma DPP4 activity in WT and Dpp4-Liv-Tg mice. Dpp4-Liv-Tg animals exhibited a 2-fold increase in plasma DPP4 activity, demonstrating an elevated release of DPP4 from livers of these mice ( Figure 2D ). In addition, cell supernatants of primary hepatocytes from Dpp4-Liv-Tg mice showed higher DPP4 concentration and activity than those from WT controls (Supplementary Figure 1C,D) . Since incretin hormones are known substrates of DPP4, we next analyzed the effect of hepatic Dpp4 overexpression on the half-life of glucagon-like peptide 1 (GLP-1). Fifteen minutes after oral glucose gavage, portal vein concentration of the active form of GLP-1 was similar in WT and Dpp4-Liv-Tg animals, indicating no differences in GLP-1 secretion from intestinal L-cells ( Figure 2E ). However, analysis of blood obtained from vena cava (after liver passage) revealed a 2-fold reduction of active GLP-1 in Dpp4-Liv-Tg mice, suggesting an increased cleavage and inactivation of GLP-1 by hepatocyte originated DPP4 ( Figure 2E ). Together, these data indicate that hepatic overexpression of Dpp4 results in elevated plasma DPP4 activity, which, in turn, leads to reduced post-prandial GLP-1 levels.