Peroxisome proliferator-activated receptorγ coactivators (PGC-1α and PGC-1β) play important roles in the transcriptional regulation of intermediary metabolism. To evaluate the effects of overexpressing PGC-1α or PGC-1β at physiologic levels in liver, we generated transgenic mice with inducible overexpression of PGC-1α or PGC-1β. Gene expression array profiling revealed that whereas both PGC-1 family proteins induced mitochondrial oxidative enzymes, the expression of several genes involved in converting glucose to fatty acid was induced by PGC-1β, but not PGC-1α. The increased expression of enzymes involved in carbohydrate utilization and de novo lipogenesis by PGC-1β required carbohydrate response element binding protein (ChREBP). The interaction between PGC-1β and ChREBP, as well as PGC-1β occupancy of the liver-type pyruvate kinase promoter, was influenced by glucose concentration and liver-specific PGC-1β-/- hepatocytes were refractory to the lipogenic response to high glucose conditions. These data suggest that PGC-1β-mediated coactivation of ChREBP is involved in the lipogenic response to hyperglycemia.
Bibliographical noteFunding Information:
The authors thank Dr. Douglas Mashek for technical advice on the high/low glucose studies with mouse hepatocytes and Dr. Geoffrey Girnun for helpful discussions. K.T.C. is supported by a Liver Scholar Award from the American Liver Foundation and a pilot and feasibility award from the Nutrition Obesity Research Center at Washington University ( P30 DK056341 ). The project was also supported by R01 DK078187 (to B.N.F.), R01 DK091538 (to P.A.C.), and DK064951 (to A.K.). The Core Centers of Washington University also supported these studies ( P30 DK056341 , P60 DK020579 , P30 DK052574 ).