Cholesterol 7 alpha-hydroxylase
Cholesterol 7 alpha-hydroxylase also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) is an enzyme that in humans is encoded by the CYP7A1 gene.[1]
Function
Cholesterol 7 alpha-hydroxylase is the rate-limiting enzyme in the synthesis of bile acid from cholesterol via the classic pathway, catalyzing the formation of 7-alpha-hydroxycholesterol. CYP7A1 is a cytochrome P450 heme enzyme that oxidizes cholesterol using molecular oxygen.
It is downregulated by Sterol regulatory element-binding proteins (SREBP) when plasma cholesterol levels are low. It is upregulated by the nuclear receptor LXR (liver X receptor) when cholesterol (to be specific, oxysterol) levels are high.[2]
The effect of this upregulation is to increase the production of bile acids and reduce the level of cholesterol in hepatocytes.
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [3]
Clinical significance
Deficiency of this enzyme will increase the possibility of cholesterol gallstones.[4]
References
- ^ Cohen JC, Cali JJ, Jelinek DF, Mehrabian M, Sparkes RS, Lusis AJ, Russell DW, Hobbs HH (September 1992). "Cloning of the human cholesterol 7 alpha-hydroxylase gene (CYP7) and localization to chromosome 8q11-q12". Genomics 14 (1): 153–61. doi:10.1016/S0888-7543(05)80298-8. PMID 1358792.
- ^ Chawla A, Saez E, Evans RM (September 2000). "Don't know much bile-ology". Cell 103 (1): 1–4. doi:10.1016/S0092-8674(00)00097-0. PMID 11051540.
- ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430". http://www.wikipathways.org/index.php/Pathway:WP430.
- ^ Paumgartner G, Sauerbruch T (November 1991). "Gallstones: pathogenesis". Lancet 338 (8775): 1117–21. doi:10.1016/0140-6736(91)91972-W. PMID 1682550.
Further reading
- Davis RA, Miyake JH, Hui TY, Spann NJ (2002). "Regulation of cholesterol-7alpha-hydroxylase: BAREly missing a SHP.". J. Lipid Res. 43 (4): 533–43. PMID 11907135.
- Kim HJ, Park HY, Kim E, et al. (2010). "Common CYP7A1 promoter polymorphism associated with risk of neuromyelitis optica.". Neurobiol. Dis. 37 (2): 349–55. doi:10.1016/j.nbd.2009.10.013. PMID 19850125.
- Holmes MV, Shah T, Vickery C, et al. (2009). Luo, Yuan. ed. "Fulfilling the promise of personalized medicine? Systematic review and field synopsis of pharmacogenetic studies.". PLoS ONE 4 (12): e7960. doi:10.1371/journal.pone.0007960. PMC 2778625. PMID 19956635. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2778625.
- Lipkin SM, Chao EC, Moreno V, et al. (2010). "Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer". Cancer Prev Res (Phila Pa) 3 (5): 597–603. doi:10.1158/1940-6207.CAPR-10-0007. PMID 20403997.
- Lambrinoudaki I, Kaparos G, Rizos D, et al. (2009). "Apolipoprotein E and paraoxonase 1 polymorphisms are associated with lower serum thyroid hormones in postmenopausal women". Clin. Endocrinol. (Oxf) 71 (2): 284–90. doi:10.1111/j.1365-2265.2008.03476.x. PMID 19018779.
- Poduri A, Khullar M, Bahl A, et al. (2009). "A combination of proatherogenic single-nucleotide polymorphisms is associated with increased risk of coronary artery disease and myocardial infarction in Asian Indians". DNA Cell Biol. 28 (9): 451–60. doi:10.1089/dna.2009.0887. PMID 19558216.
- Li T, Chanda D, Zhang Y, et al. (2010). "Glucose stimulates cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes". J. Lipid Res. 51 (4): 832–42. doi:10.1194/jlr.M002782. PMC 2842145. PMID 19965590. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2842145.
- Kovár J, Lenícek M, Zimolová M, Vítek L, Jirsa M, Pitha J (2010). "Regulation of diurnal variation of cholesterol 7alpha-hydroxylase (CYP7A1) activity in healthy subjects". Physiol Res 59 (2): 233–8. PMID 19537927.
- Chien KL, Wang KC, Chen YC, et al. (2010). "Common sequence variants in pharmacodynamic and pharmacokinetic pathway-related genes conferring LDL cholesterol response to statins". Pharmacogenomics 11 (3): 309–17. doi:10.2217/pgs.09.160. PMID 20235787.
- Saito A, Kawamoto M, Kamatani N (2009). "Association study between single-nucleotide polymorphisms in 199 drug-related genes and commonly measured quantitative traits of 752 healthy Japanese subjects". J. Hum. Genet. 54 (6): 317–23. doi:10.1038/jhg.2009.31. PMID 19343046.
- Nelson DR, Zeldin DC, Hoffman SM, et al. (2004). "Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants". Pharmacogenetics 14 (1): 1–18. doi:10.1097/00008571-200401000-00001. PMID 15128046.
- Li T, Ma H, Park YJ, et al. (2009). "Forkhead box transcription factor O1 inhibits cholesterol 7alpha-hydroxylase in human hepatocytes and in high fat diet-fed mice". Biochim. Biophys. Acta 1791 (10): 991–6. doi:10.1016/j.bbalip.2009.05.004. PMC 2743791. PMID 19463968. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2743791.
- Chakrabarti B, Dudbridge F, Kent L, et al. (2009). "Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome". Autism Research 2 (3): 157–77. doi:10.1002/aur.80. PMID 19598235.
- Barcelos AL, Chies R, Almeida SE, et al. (2009). "Association of CYP7A1 -278A>C polymorphism and the response of plasma triglyceride after dietary intervention in dyslipidemic patients". Braz. J. Med. Biol. Res. 42 (6): 487–93. PMID 19448895.
- Voora D, Shah SH, Reed CR, et al. (2008). "Pharmacogenetic predictors of statin-mediated low-density lipoprotein cholesterol reduction and dose response". Circ Cardiovasc Genet 1 (2): 100–6. doi:10.1161/CIRCGENETICS.108.795013. PMC 2995295. PMID 20031551. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2995295.
- Schwarz M, Lund EG, Russell DW (1998). "Two 7 alpha-hydroxylase enzymes in bile acid biosynthesis". Curr. Opin. Lipidol. 9 (2): 113–8. doi:10.1097/00041433-199804000-00006. PMID 9559267.
- Beigneux A, Hofmann AF, Young SG (2002). "Human CYP7A1 deficiency: progress and enigmas". J. Clin. Invest. 110 (1): 29–31. doi:10.1172/JCI16076. PMC 151039. PMID 12093884. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=151039.
- Ruaño G, Bernene J, Windemuth A, Bower B, Wencker D, Seip RL, Kocherla M, Holford TR, Petit WA, Hanks S (February 2009). "Physiogenomic comparison of edema and BMI in patients receiving rosiglitazone or pioglitazone". Clin. Chim. Acta 400 (1–2): 48–55. doi:10.1016/j.cca.2008.10.009. PMID 18996102.
- Schaap FG, van der Gaag NA, Gouma DJ, Jansen PL (2009). "High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis". Hepatology 49 (4): 1228–35. doi:10.1002/hep.22771. PMID 19185005.
- Srivastava A, Choudhuri G, Mittal B (2010). "CYP7A1 (-204 A>C; rs3808607 and -469 T>C; rs3824260) promoter polymorphisms and risk of gallbladder cancer in North Indian population". Metab. Clin. Exp. 59 (6): 767–73. doi:10.1016/j.metabol.2009.09.021. PMID 20005541.
External links
|
|
|
| CYP1 |
|
|
| CYP2 |
|
|
| CYP3 (CYP3A) |
|
|
| CYP4 |
|
|
| CYP5-20 |
CYP5 ( A1) · CYP7 (A1, B1) · CYP8 ( A1, B1) · CYP11 ( A1, B1, B2) · CYP17 ( A1) · CYP19 ( A1) · CYP20 ( A1)
|
|
| CYP21-51 |
|
|
|
|
|
| Mevalonate pathway |
|
|
| To cholesterol |
|
|
| To Bile acids |
|
|
| Steroidogenesis |
|
|
|
|
mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m
|
k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon
|
m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)
|
|
|
|
|
noco(d)/cong/tumr, sysi/epon
|
proc, drug (A10/H1/H2/H3/H5)
|
|
|
|