title: Phosphoenolpyruvate Carboxykinase, a Key Enzyme That Controls Blood Glucose, Is a Target of Retinoic Acid Receptor-Related Orphan Receptor α.
abstract: Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes a committed and rate-limiting step in hepatic gluconeogenesis, and its activity is tightly regulated to maintain blood glucose levels within normal limits. PEPCK activity is primarily regulated through hormonal control of gene transcription. Transcription is additionally regulated via a cAMP response unit, which includes a cAMP response element and four binding sites for CCAAT/enhancer-binding protein (C/EBP). Notably, the cAMP response unit also contains a putative response element for retinoic acid receptor-related orphan receptor α (RORα). In this paper, we characterize the effect of the RORα response element on cAMP-induced transcription. Electrophoresis mobility shift assay indicates that RORα binds this response element in a sequence-specific manner. Furthermore, luciferase reporter assays indicate that RORα interacts with C/EBP at the PEPCK promoter to synergistically enhance transcription. We also found that cAMP-induced transcription depends in part on RORα and its response element. In addition, we show that suppression of RORα by siRNA significantly decreased PEPCK transcription. Finally, we found that a RORα antagonist inhibits hepatic gluconeogenesis in an in vitro glucose production assay. Taken together, the data strongly suggest that PEPCK is a direct RORα target. These results define possible new roles for RORα in hepatic gluconeogenesis.
authors.affiliation: Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Science, Fukuyama University, Fukuyama, Hiroshima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuoka
authors.affiliation: Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Science, Fukuyama University, Fukuyama, Hiroshima, Japan.
authors.forename: Akiho
authors.initials: A
authors.lastname: Shima
authors.affiliation: Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Science, Fukuyama University, Fukuyama, Hiroshima, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kuramoto
authors.affiliation: Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Science, Fukuyama University, Fukuyama, Hiroshima, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kikumoto
authors.affiliation: Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Science, Fukuyama University, Fukuyama, Hiroshima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Science, Fukuyama University, Fukuyama, Hiroshima, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Michihara
mesh_terms: D001786:Blood Glucose / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D022762:CCAAT-Enhancer-Binding Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; D000242:Cyclic AMP; D019764:Phosphoenolpyruvate Carboxykinase (ATP)