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Molecular mechanism of hypoxia‐mediated hepatic gluconeogenesis by transcriptional regulation
Author(s) -
Choi Jeong Hae,
Park Min Jung,
Kim Kook Whan,
Choi Yoon Ha,
Park Sun Hee,
An Won Gun,
Yang Ung Suk,
Cheong JaeHun
Publication year - 2005
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2005.03.097
Subject(s) - phosphoenolpyruvate carboxykinase , gluconeogenesis , coactivator , transactivation , glycolysis , biology , transcription factor , regulation of gene expression , transcription (linguistics) , microbiology and biotechnology , hypoxia (environmental) , transcriptional regulation , gene expression , biochemistry , chemistry , enzyme , gene , linguistics , philosophy , organic chemistry , oxygen
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.