PGC-1alpha coactivates estrogen-related receptor-alpha to induce the expression of glucokinase.
Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) 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 ERRalpha binding site in the regulatory sequence of the glucokinase gene and that PGC-1alpha coactivates ERRalpha to stimulate the transcription of glucokinase. Simultaneous overexpression of PGC-1alpha and ERRalpha potently induced the glucokinase gene expression and its enzymatic activity in primary hepatocytes; however, expression of either PGC-1alpha or ERRalpha alone had no significant effect. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed the interaction of ERRalpha with the glucokinase promoter. Finally, the knockdown of endogenous ERRalpha with specific siRNA (siERRalpha) or pharmacological inhibition of ERRalpha with XCT790 attenuated insulin-induced glucokinase expression. Taken together, this research identifies glucokinase as a novel target of PGC-1alpha/ERRalpha and underscores the regulatory function of ERRalpha in insulin-dependent enzyme regulation.
Zhu
Liu-Luan
LL
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
Liu
Yang
Y
Cui
An-Fang
AF
Shao
Di
D
Liang
Ji-Chao
JC
Liu
Xiao-Jun
XJ
Chen
Yong
Y
Gupta
Nishith
N
Fang
Fu-De
FD
Chang
Yong-Sheng
YS
D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005941:Glucokinase / Q000096:biosynthesis* / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D016297:Mutagenesis, Site-Directed; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D012313:RNA / Q000737:chemistry / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D000097983:ERRalpha Estrogen-Related Receptor
D005941:Glucokinase; D005947:Glucose; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012313:RNA; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C501429:Ppargc1a protein, rat