title: Molecular mechanism of hypoxia-mediated hepatic gluconeogenesis by transcriptional regulation.
abstract: Until now, it is known that hypoxia increases the glycolytic enzyme expression at the transcriptional level. Here, we show evidence that hypoxia increases hepatic glucose output and HIF-1 and ATF-2-mediated transactivation of phosphoenolpyruvate carboxykinase (PEPCK), which plays a critical role as a rate-limiting enzyme in gluconeogenesis, gene in liver. HIF-1 directly bound to the specific PEPCK promoter region through its cognate binding element and found as an active complex with coactivator CBP. Additionally, ATF-2 was also involved to regulate hypoxia-dependent PEPCK transcription in the transcriptional complex with HIF-1 and CBP. Interestingly, retinoic acid (RA) signaling induced the recruitment of HIF-1 on the PEPCK promoter, resulting from the functional interaction of HIF-1 and ATF-2 with coactivator CBP. Taken together, these results suggest that hypoxia signaling leads the hepatic glucose production and release via the increased gene expression of gluconeogenic enzymes, possibly playing a role in providing glucose to other tissues, such as endothelial, brain and muscle cells.
authors.affiliation: Department of Molecular Biology, Pusan National University, Busan, Republic of Korea.
authors.forename: Jeong Hae
authors.initials: JH
authors.lastname: Choi
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Park
authors.forename: Kook Whan
authors.initials: KW
authors.lastname: Kim
authors.forename: Yoon Ha
authors.initials: YH
authors.lastname: Choi
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Park
authors.forename: Won Gun
authors.initials: WG
authors.lastname: An
authors.forename: Ung Suk
authors.initials: US
authors.lastname: Yang
authors.forename: JaeHun
authors.initials: J
authors.lastname: Cheong
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005943:Gluconeogenesis; D000860:Hypoxia / Q000201:enzymology / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D019764:Phosphoenolpyruvate Carboxykinase (ATP)