Data distribution and gene expression statistical analysis were performed using NCSS statistical and power analysis software 2007. Comparisons of two groups were performed using a Student t test followed by the Mann-Whitney U test where appropriate. P < 0.05 was considered significant. ATPβsynt, ATPβ-synthase; Cpt-1α, carnitine palmitoyl transferase-1α;

COXI, cytochrome c oxidase subunit I; cytC, cytochrome C; DNL, de novo lipogenesis; Dgat1 and 2, diacylglycerol acyltransferase 1 and 2; IL-1β, interleukin β; Idh3α, isocitrate dehydrogenase 3α; Mcad, medium-chain acyl-coenzyme A dehydrogenase; MCD, methionine and choline deficient diet; MCS, methionine and choline supplied diet; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NEFAs, nonesterified fatty acids; Scd-1, stearoyl Co-A Desaturase 1; pro-col, procollagen; Selleckchem CYC202 Tnfα, tumor necrosis factor α. In order to verify that a constitutive overexpression of PGC-1β in the liver was able to induce its target genes, we first generated a mouse model in which human PGC1-β is selectively overexpressed in the liver (LivPGC-1β mice) by subcloning the hPGC1-β Proteases inhibitor coding sequence

under the control of the apolipoprotein E promoter. The human PGC-1β is expressed only in the liver of transgenic mice (Supporting Fig. 1). In order to characterize the tissue-specific transcriptional scenario activated by PGC-1β, we performed microarray analysis of liver samples from wildtype and LivPGC-1β mice fed a chow diet. The data showed that PGC-1β coactivator overexpression is able to induce a plethora of genes involved in several metabolic pathways (Fig. 1A). The majority of target genes whose expression is enhanced by PGC-1β (1.3-fold or more) encodes for proteins involved in the mitochondrial oxidative phosphorylation. Ceramide glucosyltransferase Other pathways up-regulated

by the hepatic PGC-1β overexpression were ubiquinone and protein biosynthesis, lipid metabolism, TG transport, citrate cycle, gluconeogenesis, and antioxidant systems. These results were confirmed by real-time quantitative (qPCR) analysis of the gene expression levels of cytochrome c (cytC), a component of the respiratory chain, as well as of medium-chain acyl-coenzyme A dehydrogenase (Mcad) and carnitine palmitoyl transferase-1α (Cpt-1α), two key enzymes in fatty acid β-oxidation (Fig. 1B). Moreover, real-time qPCR analysis confirmed that overexpression of PGC1-β was associated with the induction of genes involved in lipid anabolism, including Srebp1c and its target gene, Fas, both involved in fatty acid synthesis. Notably, also the expression of Stearoyl Co-A Desaturase 1 (Scd-1) that catalyzes the biosynthesis of monounsaturated fatty acids, and diacylglycerol acyltransferase 1 and 2 (Dgat1 and 2), fundamental enzymes for TG synthesis, were increased by the overexpression of hepatic PGC1-β (Fig. 1B).