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

ve GLP-1 after liver passage, suggesting hepatic DPP4 as a major contributor in the degradation of postprandial GLP-1. Since hepatic DPP4 expression is usually confined to the bile canalicular domain, it is unlikely that DPP4 reaches the bloodstream to degrade GLP-1. However, under conditions of liver damage polarity of the cells can change leading to the release of DPP4 into interstitial fluids as described before [34] . Thus, increased plasma DPP4 activity in Dpp4-Liv-Tg mice seems not to be solely the result of elevated expression but also of changes in cell polarity as supposed from histological examinations ( Figure 2C ). In line with this, human studies have shown associations of serum DPP4 with markers for liver damage (GGT and ALT) as well as hepatocyte fibrosis and apoptosis [12, 35] . In contrast, Dpp4-knockout rats reveal lower serum AST and ALT after 2 months on a Western diet [14] , and Dpp4-deficient mice display less liver fibrosis and inflammation in an experimental model of liver injury [36] . Here, we show that hepatocyte-specific Dpp4 overexpression resulted in significant higher levels of GGT and numerical increased AST and ALT concentrations, providing further evidence for a direct connection between hepatic DPP4 and liver damage. The observed hypercholesterolemia of Dpp4-Liv-Tg mice is in line with previous studies, showing increased cholesterol levels in human subjects with elevated hepatic DPP4 [9] , and reduced plasma cholesterol levels in Dpp4deficient rats [14] . The elevated triglyceride content in livers of Dpp4-Liv-Tg mice appears to be the consequence of augmented levels of PPARg and CD36, both being implicated in liver steatosis. Similarly, exogenous DPP4 increases lipid accumulation and PPARg expression in pre-adipocytes [37] , and activation of DPP4 on the surface of macrophages by middle east respiratory syndrome corona virus (MERS-CoV) induces PPARg expression [38] . On the other hand, DPP4 was identified as PPARg target gene in cells derived from human placental tissue [39] . The mechanism of DPP4-mediated PPARg induction is still unclear, whereas effects of increased hepatic PPARg are well understood. Hepatocyte-specific expression of PPARg is associated with fatty liver in human [40] and mice [41, 42] , and hepatic overexpression of PPARg induces liver steatosis [43] , whereas PPARg-knockout reduces hepatic fat content in mice on a HFD [44] . The major targets of PPARg in the liver are fatty acid (Cd36) and monoacylglycerol O-acyltransferase 1 (Mogat1), both being implicated in fatty liver disease [45] , and upregulated in livers of Dpp4-Liv-Tg mice. Thus, high PPARg and CD36 levels in Dpp4-Liv-Tg livers seem to contribute to elevated levels of hepatic steatosis. Wronkowitz and colleagues recently identified protease-activated receptor 2 (PAR2) as DPP4 receptor [22] , which is implicated in attenuation of obesity, adipose tissue inflammation, macrophage infiltration Quantification of protein content is depicted relative to tubulin levels (n ¼ 4). The quantification for DPP4 is shown in Figure 2B . All data are represented as mean AE SEM. *p < 0.05, **p < 0.01. and insulin resistance [46, 47] . It has been shown that soluble DPP4 induces inflammation in human smooth muscle cells via MAPK and NFkB-mediated pathways [22] , and a study in primary human adipocytes revealed suppression of TNFa-induced IL6 secretion after genetic silencing of DPP4 [20] . Moreover, it was suggested that DPP4 enhances infla