PGC-1β in the regulation of hepatic glucose and energy metabolism

Abstract

Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a transcriptional coactivator that regulates multiple aspects of cellular energy metabolism, including mitochondrial biogenesis, hepatic gluconeogenesis, and β-oxidation of fatty acids. PGC-1α mRNA levels are increased in both type-1 and type-2 diabetes and may contribute to elevated hepatic glucose production in diabetic states. We have recently described PGC-1β, a novel transcriptional coactivator that is a homolog of PGC-1α. Although PGC-1β shares significant sequence similarity and tissue distribution with PGC-1α, the biological activities of PGC-1β in the regulation of cellular metabolism is unknown. In this study, we used an adenoviral-mediated expression system to study the function of PGC-1β both in cultured hepatocytes and in the liver of rats. PGC-1β, like PGC-1α, potently induces the expression of an array of mitochondrial genes involved in oxidative metabolism. However, in contrast to PGC-1α, PGC-1β poorly activates the expression of gluconeogenic genes in hepatocytes or liver in vivo, illustrating that these two coactivators play distinct roles in hepatic glucose metabolism. The reduced ability of PGC-1β to induce gluconeogenic genes is due, at least in part, to its inability to physically associate with and coactivate hepatic nuclear receptor 4α (HNF4α) and forkhead transcription factor O1 (FOXO1), two critical transcription factors that mediate the activation of gluconeogenic gene expression by PGC-1α. These data illustrate that PGC-1β and PGC-1α have distinct arrays of activities in hepatic energy metabolism.