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

Next, we performed global transcriptome profiling with RNA isolated from livers of 30-week-old WT and Dpp4-Liv-Tg mice. Microarray analysis revealed that 105 genes were up-and 60 genes downregulated in livers of Dpp4-Liv-Tg mice (log2-fold change j>0.50j, p < 0.05). Focusing on genes involved in lipid metabolism, we detected no changes in genes of triglyceride hydrolysis, de novo lipogenesis (except Srebf1), and only slightly elevated mRNA levels of Cpt1a, Apob, and Dgat2 in Dpp4-Liv-Tg mice (Supplementary Figure 3) . The most striking effect was observed for the transcription factor peroxisome proliferator activated receptor gamma (Pparg) and its downstream target fatty acid translocase (Cd36), which were both significantly increased in livers of Dpp4-Liv-Tg mice (2.2-fold and 2.3fold, Supplementary Figure 3 ). Monoacylglycerol O-acyltransferase 1 (Mogat1), another target gene of hepatocyte PPARg, also tended to be higher in Dpp4-Liv-Tg mice (Supplementary Figure 3) . Validation using quantitative real-time PCR confirmed a significantly elevated expression of Pparg and Cd36 and a trend towards higher Mogat1 levels in transgenic animals ( Figure 5A ). In agreement, western blot analysis showed higher PPARg and CD36 protein levels in livers of Dpp4-Liv-Tg animals ( Figure 5B ). Interestingly, only PPARg isoform 1 was upregulated in these samples, suggesting an isoform-specific effect of DPP4 on PPARg expression. In summary, DPP4-induced liver steatosis associates with elevated hepatic PPARg and CD36 expression.