Abstract

Objective: The peroxisome proliferator-activated receptor-γ coactivator (PGC)-1 family of transcriptional co-activators controls hepatic function by modulating the expression of key metabolic enzymes. Hepatic gain of function and complete genetic ablation of PGC-1α show that this co-activator 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-1α activity affect metabolism and energy homeostasis has yet to be determined.

Research Method and Design: To identify key metabolic pathways that may be physiologically relevant in the context of reduced hepatic PGC-1α levels, we have employed the cre/lox system to create mice heterozygous for PGC-1α 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 β-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 in LH mice fed a high fat diet and primary hepatocytes.

Conclusions: These data highlight both the dose-dependent and long-term effects of reducing hepatic PGC-1α levels; underlining the importance of tightly regulated PGC-1α expression in the maintenance of lipid homeostasis and glucose metabolism.