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Hypoxic repression of CYP7A1 through a HIF-1α- and SHP-independent mechanism
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  • Journal title : BMB Reports
  • Volume 49, Issue 3,  2016, pp.173-178
  • Publisher : Korean Society for Biochemistry and Molecular Biology
  • DOI : 10.5483/BMBRep.2016.49.3.188
 Title & Authors
Hypoxic repression of CYP7A1 through a HIF-1α- and SHP-independent mechanism
Moon, Yunwon; Park, Bongju; Park, Hyunsung;
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Liver cells experience hypoxic stress when drug-metabolizing enzymes excessively consume O2 for hydroxylation. Hypoxic stress changes the transcription of several genes by activating a heterodimeric transcription factor called hypoxia-inducible factor-1α/β (HIF-1α/β). We found that hypoxic stress (0.1% O2) decreased the expression of cytochrome P450 7A1 (CYP7A1), a rate-limiting enzyme involved in bile acid biosynthesis. Chenodeoxycholic acid (CDCA), a major component of bile acids, represses CYP7A1 by activating a transcriptional repressor named small heterodimer partner (SHP). We observed that hypoxia decreased the levels of both CDCA and SHP, suggesting that hypoxia repressed CYP7A1 without inducing SHP. The finding that overexpression of HIF-1α increased the activity of the CYP7A1 promoter suggested that hypoxia decreased the expression of CYP7A1 in a HIF-1-independent manner. Thus, the results of this study suggested that hypoxia decreased the activity of CYP7A1 by limiting its substrate O2, and by decreasing the transcription of CYP7A1.
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Medium-chain fatty acids reduce serum cholesterol by regulating the metabolism of bile acid in C57BL/6J mice, Food Funct., 2017, 8, 1, 291  crossref(new windwow)
Nath B and Szabo G (2012) Hypoxia and hypoxia inducible factors: diverse roles in liver diseases. Hepatology 55, 622-633 crossref(new window)

Jungermann K and Kietzmann T (2000) Oxygen: modulator of metabolic zonation and disease of the liver. Hepatology 31, 255-260 crossref(new window)

Arteel GE, Iimuro Y, Yin M, Raleigh JA and Thurman RG (1997) Chronic enteral ethanol treatment causes hypoxia in rat liver tissue in vivo. Hepatology 25, 920-926 crossref(new window)

Masson N and Ratcliffe PJ (2003) HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O(2) levels. J Cell Sci 116, 3041-3049 crossref(new window)

Bruick RK and McKnight SL (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337-1340 crossref(new window)

Jaakkola P, Mole DR, Tian YM et al (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468-472 crossref(new window)

Kallio PJ, Wilson WJ, O'Brien S, Makino Y and Poellinger L (1999) Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway. J Biol Chem 274, 6519-6525 crossref(new window)

Park KC, Lee DC and Yeom YI (2015) NDRG3-mediated lactate signaling in hypoxia. BMB Rep 48, 301-302 crossref(new window)

Kim I, Ahn SH, Inagaki T et al (2007) Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res 48, 2664-2672 crossref(new window)

Davis RA, Miyake JH, Hui TY and Spann NJ (2002) Regulation of cholesterol-7alpha-hydroxylase: BAREly missing a SHP. J Lipid Res 43, 533-543

Bavner A, Sanyal S, Gustafsson JA and Treuter E (2005) Transcriptional corepression by SHP: molecular mechanisms and physiological consequences. Trends Endocrinol Metab 16, 478-488 crossref(new window)

Garruti G, Wang HH, Bonfrate L, de Bari O, Wang DQ and Portincasa P (2012) A pleiotropic role for the orphan nuclear receptor small heterodimer partner in lipid homeostasis and metabolic pathways. J Lipids 2012, 304292

Kerr TA, Saeki S, Schneider M et al (2002) Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev Cell 2, 713-720 crossref(new window)

Kim ND, Im EO, Choi YH and Yoo YH (2002) Synthetic bile acids: novel mediators of apoptosis. J Biochem Mol Biol 35, 134-141 crossref(new window)

Noshiro M, Usui E, Kawamoto T et al (2007) Multiple mechanisms regulate circadian expression of the gene for cholesterol 7alpha-hydroxylase (Cyp7a), a key enzyme in hepatic bile acid biosynthesis. J Biol Rhythms 22, 299-311 crossref(new window)

Park YK and Park H (2012) Differentiated embryo chondrocyte 1 (DEC1) represses PPARgamma2 gene through interacting with CCAAT/enhancer binding protein beta (C/EBPbeta). Mol Cells 33, 575-581 crossref(new window)

Choi SM, Cho HJ, Cho H, Kim KH, Kim JB and Park H (2008) Stra13/DEC1 and DEC2 inhibit sterol regulatory element binding protein-1c in a hypoxia-inducible factor-dependent mechanism. Nucleic Acids Res 36, 6372-6385 crossref(new window)

Ramakrishnan SK, Taylor M, Qu A et al (2014) Loss of von Hippel-Lindau protein (VHL) increases systemic cholesterol levels through targeting hypoxia-inducible factor 2alpha and regulation of bile acid homeostasis. Mol Cell Biol 34, 1208-1220 crossref(new window)

Shinkyo R and Guengerich FP (2011) Cytochrome P450 7A1 cholesterol 7alpha-hydroxylation: individual reaction steps in the catalytic cycle and rate-limiting ferric iron reduction. J Biol Chem 286, 4632-4643 crossref(new window)

Berchner-Pfannschmidt U, Tug S, Trinidad B et al (2008) Nuclear oxygen sensing: induction of endogenous prolyl-hydroxylase 2 activity by hypoxia and nitric oxide. J Biol Chem 283, 31745-31753 crossref(new window)

Choi SM, Oh H and Park H (2008) Microarray analyses of hypoxia-regulated genes in an aryl hydrocarbon receptor nuclear translocator (Arnt)-dependent manner. FEBS J 275, 5618-5634 crossref(new window)

Lee HY, Choi K, Oh H, Park YK and Park H (2014) HIF-1-dependent induction of Jumonji domain-containing protein (JMJD) 3 under hypoxic conditions. Mol Cells 37, 43-50 crossref(new window)

Lee HY, Yang EG and Park H (2013) Hypoxia enhances the expression of prostate-specific antigen by modifying the quantity and catalytic activity of Jumonji C domain-containing histone demethylases. Carcinogenesis 34, 2706-2715 crossref(new window)

Hur E, Kim HH, Choi SM et al (2002) Reduction of hypoxia-induced transcription through the repression of hypoxia-inducible factor-1alpha/aryl hydrocarbon receptor nuclear translocator DNA binding by the 90-kDa heat-shock protein inhibitor radicicol. Mol Pharmacol 62, 975-982 crossref(new window)

Bhalla S, Ozalp C, Fang S, Xiang L and Kemper JK (2004) Ligand-activated pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1alpha. Functional implications in hepatic cholesterol and glucose metabolism. J Biol Chem 279, 45139-45147 crossref(new window)

Lee J, Son J, Lee M, Lee KT and Kim DH (2003) Simultaneous quantitation of enalapril and enalaprilat in human plasma by 96-well solid-phase extraction and liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 17, 1157-1162 crossref(new window)