Hyperlipidemic Effects of Dietary Saturated Fats Mediated through PGC-1(beta) Coactivation of SREBP

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-1(beta) and SREBP1c and 1a in liver. PGC-1(beta) coactivates the SREBP transcription factor family and stimulates lipogenic gene expression. Further, PGC-1(beta) is required for SREBP-mediated lipogenic gene expression. However, unlike SREBP itself, PGC-1(beta) reduces fat accumulation in the liver while greatly increasing circulating triglycerides and cholesterol in VLDL particles. The stimulation of lipoprotein transport upon PGC-1(beta) expression is likely due to the simultaneous coactivation of the liver X receptor, LXR(alpha), 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.