The PGC-1 family of coactivators stimulates the activity of certain transcription factors and nuclear receptors. Transcription factors in the sterol responsive element binding protein (SREBP) family are key regulators of the lipogenic genes in the liver. We show here that high-fat feeding, which induces hyperlipidemia and atherogenesis, stimulates the expression of both PGC-1beta and SREBP1c and 1a in liver. PGC-1beta coactivates the SREBP transcription factor family and stimulates lipogenic gene expression. Further, PGC-1beta is required for SREBP-mediated lipogenic gene expression. However, unlike SREBP itself, PGC-1beta reduces fat accumulation in the liver while greatly increasing circulating triglycerides and cholesterol in VLDL particles. The stimulation of lipoprotein transport upon PGC-1beta expression is likely due to the simultaneous coactivation of the liver X receptor, LXRalpha, a nuclear hormone receptor with known roles in hepatic lipid transport. These data suggest a mechanism through which dietary saturated fats can stimulate hyperlipidemia and atherogenesis.

Peroxisome proliferator-activated receptor ␥ coactivator (PGC)-1␣ is a coactivator of nuclear receptors and other transcription factors that regulates several components of energy metabolism, particularly certain aspects of adaptive thermogenesis in brown fat and skeletal muscle, hepatic gluconeogenesis, and fiber type switching in skeletal muscle. PGC-1␣ has been shown to induce mitochondrial biogenesis when expressed in muscle cells, and preliminary analysis has suggested that this molecule may specifically increase the fraction of uncoupled versus coupled respiration. In this paper, we have performed detailed bioenergetic analyses of the function of PGC-1␣ and its homolog PGC-1␤ in muscle cells by monitoring simultaneously oxygen consumption and membrane potential. Cells expressing PGC-1␣ or PGC-1␤ display higher proton leak rates at any given membrane potential than control cells. However, cells expressing PGC-1␣ have a higher proportion of their mitochondrial respiration linked to proton leak than cells expressing PGC-1␤. Although these two proteins cause a similar increase in the expression of many mitochondrial genes, PGC-1␤ preferentially induces certain genes involved in the removal of reactive oxygen species, recently recognized as activators of uncoupling proteins. Together, these data indicate that PGC-1␣ and PGC-1␤ profoundly alter mitochondrial metabolism and suggest that these proteins are likely to play different physiological functions.Mitochondria play a central role in metabolism by coupling cellular respiration to the production of ATP. However, this coupling is not perfectly tight. Indeed, it is estimated that approximately 20% of the standard metabolic rate in mammals is due to a leak of protons across the mitochondrial inner membrane in a manner that uncouples cellular respiration from ATP production, thereby generating heat (1). This cycle is called basal proton leak. In addition to this basal leak, there is an inducible leak of protons catalyzed by uncoupling protein 1 (UCP1) 1 in brown fat. Two close homologs of this protein have been discovered, UCP2 and UCP3 (2-6). Although the function of these homologs is not clear, recent work suggests that they might have an important role in the protection against reactive oxygen species (ROS) (7, 8) and the modulation of cellular ATP levels, especially in insulin-secreting ␤ cells (9, 10). Interestingly, none of the genetic studies using either knockout mice or mice overexpressing moderate levels of UCP2 and UCP3 show a significant effect of these proteins in determining standard metabolic rate by uncoupling cellular respiration (11, 12).Many changes in the cellular environment result in modulation of mitochondrial metabolism. Basal proton leak rate changes in response to hormonal status and metabolic depression (13-19). Also, small mammals with high standard metabolic rates have higher proton leak rates than large mammals with low standard metabolic rates (20,21). Furthermore, proton leak rates differ between phylogenetic groups; it is higher i...