PGC-1β and ChREBP partner to cooperatively regulate hepatic lipogenesis in a glucose concentration-dependent manner

Peroxisome proliferator-activated receptory coactivators (PGC-1 alpha and PGC-1 beta) play important roles in the transcriptional regulation of intermediary metabolism. To evaluate the effects of overexpressing PGC-1 alpha or PGC-1 beta at physiologic levels in liver, we generated transgenic mice with inducible overexpression of PGC-1 alpha or PGC-1 beta. 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-1 beta, but not PGC-1 alpha. The increased expression of enzymes involved in carbohydrate utilization and de novo lipogenesis by PGC-1 beta required carbohydrate response element binding protein (ChREBP). The interaction between PGC-1 beta and ChREBP, as well as PGC-1 beta occupancy of the liver-type pyruvate kinase promoter, was influenced by glucose concentration and liver-specific PGC-1 beta(-/-) hepatocytes were refractory to the lipogenic response to high glucose conditions. These data suggest that PGC-1 beta-mediated coactivation of ChREBP is involved in the lipogenic response to hyperglycemia. (C) 2013 Elsevier GmbH. Open access under CC BY-NC-ND license