Abstract
Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator that regulates multiple aspects of cellular energy metabolism, including mitochondrial biogenesis, hepatic gluconeogenesis, and beta-oxidation of fatty acids. PGC-1alpha 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-1beta, a novel transcriptional coactivator that is a homolog of PGC-1alpha. Although PGC-1beta shares significant sequence similarity and tissue distribution with PGC-1alpha, the biological activities of PGC-1beta in the regulation of cellular metabolism is unknown. In this study, we used an adenoviral-mediated expression system to study the function of PGC-1beta both in cultured hepatocytes and in the liver of rats. PGC-1beta, like PGC-1alpha, potently induces the expression of an array of mitochondrial genes involved in oxidative metabolism. However, in contrast to PGC-1alpha, PGC-1beta 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-1beta to induce gluconeogenic genes is due, at least in part, to its inability to physically associate with and coactivate hepatic nuclear receptor 4alpha (HNF4alpha) and forkhead transcription factor O1 (FOXO1), two critical transcription factors that mediate the activation of gluconeogenic gene expression by PGC-1alpha. These data illustrate that PGC-1beta and PGC-1alpha have distinct arrays of activities in hepatic energy metabolism.
Highlights
Liver is a key organ in the maintenance of systemic glucose homeostasis in mammals
Expression of PGC-1␣ and PGC-1 in Hepatic Development and Diabetes—The ability to activate gluconeogenesis, -oxidation of fatty acids, and ketogenesis are all characteristic of mature hepatocytes, which are functionally different from the embryonic liver cells; the embryonic liver is primarily responsible for hematopoiesis during fetal development and undergoes many metabolic changes just before and after birth [22]
To determine whether the PGC-1 coactivators may play a role in the metabolic maturation of hepatocytes, the expression of PGC-1␣ and PGC-1 mRNA was examined at different stages of mouse liver development
Summary
Liver is a key organ in the maintenance of systemic glucose homeostasis in mammals. The liver keeps blood glucose levels nearly constant under various nutritional conditions and provides a crucial source of fuel for the function of many organs and tissues under conditions of food deprivation. Hepatic expression of PGC-1␣ mRNA and protein is minimal under fed conditions, the abundance of PGC-1␣ is rapidly increased in response to fasting. Adenoviral-mediated expression of PGC-1␣ to the levels observed in livers of fasted animals activates the entire program of gluconeogenesis in both cultured primary hepatocytes and live rats. Hepatic mRNA for PGC-1, like PGC-1␣, is increased in response to fasting; the biological function of this coactivator in the regulation of cellular energy metabolism or gluconeogenesis has not been determined. We use adenoviral-mediated expression of PGC-1 to assess its role in the regulation of hepatic energy metabolism, in particular the genetic programs of gluconeogenesis and mitochondrial metabolism.
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