Therefore, hepatic expression of Cidea resulted in increased lipid storage and the accumulation of large LDs in the liver. To further evaluate the physiological

role of Cidea in the formation of hepatic steatosis, we treated Cidea-deficient mice with an ND or HFD. Under the ND feeding Buparlisib condition, liver morphology and levels of hepatic TAGs were similar between WT and Cidea−/− mice (Fig. 2A,B). However, when fed with a HFD, livers of Cidea−/− mice contained lower amounts of lipids (approximately 40% lower) and fewer and smaller LDs (Fig. 2A,B). The decreased expression of PPARγ and genes in the FA-synthesis pathway (acetyl-coenzyme A carboxylase 1 [ACC1], fatty acid synthase [FAS], and elongation of very-long-chain fatty acids protein 6 [ELOVL6]) was observed in livers of HFD-fed Cidea−/− mice (Supporting Fig. 2A), whereas expression levels of genes in the FA β-oxidation, oxidative phosphorylation, and lipolysis pathways were similar between WT and Cidea−/− mice (Supporting Fig. 2A). buy XAV-939 mRNA levels of SREBP1c were slightly decreased (Supporting Fig. 2A). However, protein levels of mature nuclear form of SREBP1c were significantly decreased (Supporting Fig. 2B), correlating well with the

decreased expression of FAS and ACC. Consistent with a previous report,15 levels of TAGs and sizes of LDs in BAT and WAT of Cidea−/− mice were lower than those in WT mice fed with a HFD (Supporting Fig. 2C,D). These data indicate that a Cidea deficiency

resulted in reduced hepatic lipid accumulation and alleviated HFD-induced hepatic steatosis. To further confirm the roles of Cidea in controlling hepatic steatosis, we generated Cidea and leptin double-deficient (ob/ob/Cidea−/−) mice. Livers of ob/ob/Cidea−/− mice had smaller and fewer find more LDs (Fig. 2C) and decreased levels of TAGs and cholesterol esters (CEs) (Fig. 2D,E). Interestingly, expression levels of SREBP1c, PPARα/γ, and de novo synthesis genes of FAs were significantly decreased in livers of the ob/ob/Cidea−/− mice (Fig. 2F). Expression levels of hepatic genes in lipolysis and mitochondrial oxidation pathways were similar between ob/ob and ob/ob/Cidea−/− mice (Supporting Fig. 3A). In addition, levels of TAGs and sizes of LDs were reduced in BAT of ob/ob/Cidea−/− mice relative to those of ob/ob mice (Supporting Fig. 3B,C). Consistent with the similar levels of hepatic Cideb in WT and ob/ob mice (Fig. 1A), sizes of LDs and levels of TAGs and CEs in livers of Cideb and leptin double-deficient (ob/ob/Cideb−/−) mice were similar to those in ob/ob mice (Fig. 2C-E). Overall, these data indicate that a Cidea deficiency results in reduced lipid accumulation and ameliorates the hepatic steatosis induced by an HFD or a leptin deficiency.