PGC-1 alpha coactivates estrogen-related receptor-alpha to induce the expression of glucokinase

Zhu L, Liu Y, Cui A, Shao D, Liang J, Liu X, Chen Y, Gupta N, Fang F, Chang Y. PGC-1 alpha coactivates estrogen-related receptor-alpha to induce the expression of glucokinase. Am J Physiol Endocrinol Metab 298: E1210-E1218, 2010. First published March 9, 2010; doi:10.1152/ajpendo.00633.2009.-Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) is a key regulator of cellular energy metabolism and regulates processes such as adaptive thermogenesis, hepatic gluconeogenesis, fatty acid oxidation, and mitochondrial biogenesis by coactivating numerous nuclear receptors and transcription factors. Here, we demonstrate the presence of the ERR alpha binding site in the regulatory sequence of the glucokinase gene and that PGC-1 alpha coactivates ERR alpha to stimulate the transcription of glucokinase. Simultaneous overexpression of PGC-1 alpha and ERR alpha potently induced the glucokinase gene expression and its enzymatic activity in primary hepatocytes; however, expression of either PGC-1 alpha or ERR alpha alone had no significant effect. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed the interaction of ERR alpha with the glucokinase promoter. Finally, the knockdown of endogenous ERR alpha with specific siRNA (siERR alpha) or pharmacological inhibition of ERR alpha with XCT790 attenuated insulin-induced glucokinase expression. Taken together, this research identifies glucokinase as a novel target of PGC-1 alpha/ERR alpha and underscores the regulatory function of ERR alpha in insulin-dependent enzyme regulation.