Expression of PPAR-α target genes did not change in cells transfected with mutant IRF9 plasmids (Supporting Fig. 6B). When we further overexpressed IRF9 specifically in the liver, we observed up-regulation of PPAR-α target genes in livers of both diet-induced and genetically obese mice (Supporting Fig. 6C,D). www.selleckchem.com/products/DMXAA(ASA404).html Taken together, these results suggest that IRF9 activates PPAR-α target gene expression by interacting with PPAR-α. As expected, primary mouse hepatocytes trasfected with PPAR-α had markedly higher levels of its target genes

than those transfected with GFP controls (Supporting Fig. 7A). To determine the sufficiency of PPAR-α in mediating the metabolic functions of IRF9, we overexpressed PPAR-α specifically in livers of WT mice and IRF9 KO mice. We injected mice with PPAR-α adenovirus through

the jugular vein. Four weeks later, PPAR-α and its target genes were significant increased in the liver (Supporting Fig. 7B,C). After 24 weeks of HFD feeding, IRF9 KO mice displayed aggravated hepatic steatosis, IR, and inflammation, as described earlier. However, after PPAR-α was overexpressed, IRF9 KO mice displayed reduced liver weight (Fig. 7A). H&E and Oil Red O staining BIBW2992 order confirmed less hepatic lipid accumulation (Fig. 7B). Lower hepatic lipid content and preserved liver function indicated attenuated steatohepatitis (Supporting Fig. 7D,E). Fasting serum glucose and insulin levels and the HOMA-IR index in PPAR-α-overexpressed

IRF9 KO mice were similar to those of GFP adenovirus-infected controls (Fig. 7C). Similar results were obtained with IPGTTs and IPITTs (Fig. 7D and 7E). Insulin signaling was also up-regulated upon PPAR-α overexpression (Fig. 7F). Measurement of inflammation- related genes by real-time PCR indicated a shifting macrophage population from M1 to M2 (Supporting Fig. 7F,G). Thus, we demonstrated that liver-specific PPAR-α overexpression rescues insulin sensitivity and ameliorates hepatic steatosis and inflammation in IRF9 Mannose-binding protein-associated serine protease KO mice. IRF9 KO mice have a relatively normal physical appearance, but are susceptible to virus infection because of the crucial role of IRF9 in mediating type I IFN responses.[21, 29] Therefore, most studies on IRF9 have been focused on its involvement in innate immunity and oncogenesis.[11] However, whether IRF9 is involved in the regulation of metabolism is unclear. In the present study, we, for the first time, demonstrated a critical role for IRF9 in hepatic lipid homeostasis. IRF9 expression was lower in livers of both diet-induced and genetic obesity models. On an HFD, IRF9 KO mice exhibited more-severe obesity, hepatic steatosis, IR, and inflammation. When IRF9 was specifically overexpressed in the liver, diet-induced and genetically obese mice displayed attenuated hepatic steatosis, IR, and inflammation, which indicate that IRF9 has an antidiabetic role.