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

To further investigate whether an increased Dpp4 expression in the liver leads to hepatic steatosis or is a consequence of the elevated lipid accumulation, we studied the development of fatty liver in WT and Dpp4-Liv-Tg mice by computed tomography. At a young age (6 weeks), both WT and Dpp4-Liv-Tg mice showed a low liver fat content of about 1.5% ( Figure 4A ). However, after 15 weeks of HFD feeding hepatic fat content raised to 4.2 AE 1.0% in Dpp4-Liv-Tg mice, whereas liver fat content in WT mice was unchanged (1.8 AE 0.2%) ( Figure 4A ). After additional 8 weeks on the diet, liver fat content reached 6.4 AE 1.6% in Dpp4-Liv-Tg and 3.1 AE 0.4% in WT mice (p < 0.01) (Figure 4A) , indicating a slow but direct effect of hepatic DPP4 levels on liver steatosis. At 30 weeks of age, liver glycogen and liver cholesterol were not significantly different, whereas levels of triglycerides were higher in Dpp4-Liv-Tg mice ( Figure 4B ). As a consequence, liver weight showed a tendency to be higher than of WT mice (Figure 4 B) . Histological examinations confirmed the increased accumulation of ectopic fat ( Figure 4C ,D) and larger lipid droplets, indicated by staining of the lipid droplet coating protein perilipin 2 in livers of Dpp4-Liv-Tg mice ( Figure 4E ). Plasma analysis of markers for liver damage showed significantly elevated levels of gamma-glutamyl transpeptidase (GGT, p < 0.05) and numerical increased alanine aminotransferase (ALT, p ¼ 0.171) and aspartate aminotransferase (AST, p ¼ 0.132) levels (Table 1) . However, markers for inflammation and fibrosis were similar in livers of WT and Dpp4-Liv-Tg animals (Supplementary Figure 2) . Taken together, elevated levels of DPP4 in the liver cause hepatic steatosis with indications of liver damage but not inflammation and fibrosis in mice on a HFD.