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

3.2. Liver-specific Dpp4 overexpression results in elevated plasma DPP4 activity and diminished GLP-1 levels To investigate whether elevated levels of DPP4 in fatty livers are cause or consequence of the disease, we generated a transgenic mouse model with a hepatocyte-specific Dpp4 overexpression. Male C57BL/ 6J wild-type (WT) and Dpp4-transgenic (Dpp4-Liv-Tg) mice received a HFD (45 kcal% from fat) for 27 weeks and were sacrificed at 30 weeks of age. Both Dpp4 mRNA and protein contents were significantly increased (2.2-fold and 1.6-fold, respectively) in livers of Dpp4-Liv-Tg mice but not altered in adipose depots or skeletal muscle (Figure 2A,B) . Primary hepatocytes isolated from Dpp4-Liv-Tg mice also showed elevated DPP4 protein content and cellular DPP4 activity than those isolated from WT animals ( Figure 2B, Supplementary Figure 1A ,B). Moreover, comparing endogenous DPP4 levels in different metabolic tissues of WT mice reveal the highest expression of DPP4 in the liver (Figure 2A,B) . Immunohistochemical staining of DPP4 in liver sections suggests increased membrane localization in Dpp4-Liv-Tg mice indicated by a co-staining with the plasma membrane marker E-cadherin , and plasma DPP4 activity (C) of ageand sex-matched subjects with or without (control) NAFLD. Data are represented as mean AE SEM (n ¼ 75e77). One-tailed t-test was performed to test whether liver fat, insulin sensitivity index, and plasma DPP4 activity are increased in NAFLD subjects. *p < 0.05, ***p < 0.001.