Sensitivity of Lipid Metabolism and Insulin Signaling to Genetic Alterations in Hepatic Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Expression

OBJECTIVE-The peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1 family of transcriptional coactivators controls hepatic function by modulating the expression of key metabolic enzymes. Hepatic gain of function and complete genetic ablation of PGC-1 alpha show that this coactivator is important for activating the programs of gluconeogenesis, fatty acid oxidation, oxidative phosphorylation, and lipid secretion during times of nutrient deprivation. However, how moderate changes in PGC-1 alpha activity affect metabolism and energy homeostasis has yet to be determined. RESEARCH DESIGN AND METHODS-To identify key metabolic pathways that may be physiologically relevant in the context of reduced hepatic PGC-1 alpha levels, we used the Cre/Lox system to create mice heterozygous for PGC-1 alpha specifically within the liver (LH mice). RESULTS-These mice showed fasting hepatic steatosis and diminished ketogenesis associated with decreased expression of genes involved in mitochondrial beta-oxidation. LH mice also exhibited high circulating levels of triglyceride that correlated with increased expression of genes involved in triglyceride-rich lipoprotein assembly. Concomitant with defects in lipid metabolism, hepatic insulin resistance was observed both in LH mice fed a high-fat diet as well as in primary hepatocytes. CONCLUSIONS-These data highlight both the dose-dependent and long-term effects of reducing hepatic PGC-1 alpha levels, underlining the importance of tightly regulated PGC-1 alpha expression in the maintenance of lipid homeostasis and glucose metabolism. Diabetes 58:1499-1508, 2009