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CYP7A1  -  cytochrome P450, family 7, subfamily A,...

Homo sapiens

Synonyms: CP7A, CYP7, CYPVII, Cholesterol 7-alpha-hydroxylase, Cholesterol 7-alpha-monooxygenase, ...
 
 
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Disease relevance of CYP7A1

 

High impact information on CYP7A1

  • The expression of LDL receptors was increased by 180 percent (P less than 0.005), whereas the activities of cholesterol 7 alpha-hydroxylase (which governs bile acid synthesis) and of acyl-coenzyme A:cholesterol O-acyltransferase (which regulates cholesterol esterification) were unaffected by treatment [6].
  • Although bile acids activate the farnesoid X receptor (FXR), the mechanism underlying bile acid-mediated repression of CYP7A1 remained unclear [7].
  • The catabolism of cholesterol into bile acids is regulated by oxysterols and bile acids, which induce or repress transcription of the pathway's rate-limiting enzyme cholesterol 7alpha-hydroxylase (CYP7A1) [8].
  • Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype [9].
  • DNA sequencing revealed two linked polymorphisms in the 5' flanking region of CYP7 [10].
 

Chemical compound and disease context of CYP7A1

  • We examined if stabilization of mRNA decay could account for the >20-fold increase in the expression of CYP7A1 mRNA without a detectable change in transcription following dexamethasone treatment of rat hepatoma cells (L35 cells) [11].
  • L-T3 decreased chloramphenicol acetyltransferase activity in hepatoma cells cotransfected with a plasmid encoding the T3 receptor (TR) alpha [NR1a1] and a chimeric gene containing nucleotides -372 to +61 of the human CYP7A1 gene fused to the chloramphenicol acetyltransferase structural gene [12].
  • To retrace the evolution of the molecular mechanisms underlying CYP7A1 inhibition, we used a chicken hepatoma cell system that retains the ability to be induced by phenobarbital and other drugs [13].
  • Competitive inhibition of bile acid synthesis by endogenous cholestanol and sitosterol in sitosterolemia with xanthomatosis. Effect on cholesterol 7 alpha-hydroxylase [14].
  • Patients with sitosterolemia with xanthomatosis, who have elevated microsomal cholestanol and sitosterol, showed reduced cholesterol 7 alpha-hydroxylase activity relative to the activity in control subjects (13.9 and 14.7 vs. 20.3 +/- 0.9 pmol/nmol P-450 per min, P less than 0.01) [14].
 

Biological context of CYP7A1

 

Anatomical context of CYP7A1

 

Associations of CYP7A1 with chemical compounds

 

Physical interactions of CYP7A1

  • In particular we show that the hamster CYP7A1 insulin response sequence is part of a complex unit involved in specific interactions with multiple transcription factors such as members of the HNF-3 family; this region does not bind very strongly to HNF-3 and as a consequence partly contributes to the transactivation of the gene [24].
 

Regulatory relationships of CYP7A1

  • The objective of this study is to elucidate the mechanism by which PXR inhibits CYP7A1 gene transcription [25].
  • Recent studies show there is an "FXR/SHP-independent" mechanism that also represses CYP7A1 expression [26].
  • The goal of this study is to elucidate the mechanism of CYP7A1 transcription by bile acid-activated farnesoid X receptor (FXR) in its native promoter and cellular context and to identify FXR response elements in the gene [27].
  • In the liver, the liver X receptor alpha induces the cholesterol 7alpha-hydroxylase (CYP7A1) gene, which controls the rate-limiting step in bile acid synthesis, the major cholesterol excretion pathway [28].
  • This DR1 sequence was mapped previously as a binding site for the hepatocyte nuclear factor 4 (HNF-4) which stimulates CYP7A1 transcription [29].
 

Other interactions of CYP7A1

 

Analytical, diagnostic and therapeutic context of CYP7A1

References

  1. PGC-1alpha activates CYP7A1 and bile acid biosynthesis. Shin, D.J., Campos, J.A., Gil, G., Osborne, T.F. J. Biol. Chem. (2003) [Pubmed]
  2. Regulation of the human cholesterol 7alpha-hydroxylase gene (CYP7A1) by thyroid hormone in transgenic mice. Drover, V.A., Agellon, L.B. Endocrinology (2004) [Pubmed]
  3. Decreased hepatic expression of PPAR-gamma coactivator-1 in cholesterol cholelithiasis. Bertolotti, M., Gabbi, C., Anzivino, C., Mitro, N., Godio, C., De Fabiani, E., Crestani, M., Del Puppo, M., Ricchi, M., Carulli, L., Rossi, A., Loria, P., Carulli, N. Eur. J. Clin. Invest. (2006) [Pubmed]
  4. Cholesterol and hepatic lipoprotein assembly and secretion. Kang, S., Davis, R.A. Biochim. Biophys. Acta (2000) [Pubmed]
  5. Oxysterol 7 alpha-hydroxylase activity by cholesterol 7 alpha-hydroxylase (CYP7A). Norlin, M., Andersson, U., Björkhem, I., Wikvall, K. J. Biol. Chem. (2000) [Pubmed]
  6. Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol. Reihnér, E., Rudling, M., Ståhlberg, D., Berglund, L., Ewerth, S., Björkhem, I., Einarsson, K., Angelin, B. N. Engl. J. Med. (1990) [Pubmed]
  7. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Goodwin, B., Jones, S.A., Price, R.R., Watson, M.A., McKee, D.D., Moore, L.B., Galardi, C., Wilson, J.G., Lewis, M.C., Roth, M.E., Maloney, P.R., Willson, T.M., Kliewer, S.A. Mol. Cell (2000) [Pubmed]
  8. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Lu, T.T., Makishima, M., Repa, J.J., Schoonjans, K., Kerr, T.A., Auwerx, J., Mangelsdorf, D.J. Mol. Cell (2000) [Pubmed]
  9. Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. Pullinger, C.R., Eng, C., Salen, G., Shefer, S., Batta, A.K., Erickson, S.K., Verhagen, A., Rivera, C.R., Mulvihill, S.J., Malloy, M.J., Kane, J.P. J. Clin. Invest. (2002) [Pubmed]
  10. Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations. Wang, J., Freeman, D.J., Grundy, S.M., Levine, D.M., Guerra, R., Cohen, J.C. J. Clin. Invest. (1998) [Pubmed]
  11. One or more labile proteins regulate the stability of chimeric mRNAs containing the 3'-untranslated region of cholesterol-7alpha -hydroxylase mRNA. Baker, D.M., Wang, S.L., Bell, D.J., Drevon, C.A., Davis, R.A. J. Biol. Chem. (2000) [Pubmed]
  12. A distinct thyroid hormone response element mediates repression of the human cholesterol 7alpha-hydroxylase (CYP7A1) gene promoter. Drover, V.A., Wong, N.C., Agellon, L.B. Mol. Endocrinol. (2002) [Pubmed]
  13. Species-specific mechanisms for cholesterol 7alpha-hydroxylase (CYP7A1) regulation by drugs and bile acids. Handschin, C., Gnerre, C., Fraser, D.J., Martinez-Jimenez, C., Jover, R., Meyer, U.A. Arch. Biochem. Biophys. (2005) [Pubmed]
  14. Competitive inhibition of bile acid synthesis by endogenous cholestanol and sitosterol in sitosterolemia with xanthomatosis. Effect on cholesterol 7 alpha-hydroxylase. Shefer, S., Salen, G., Nguyen, L., Batta, A.K., Packin, V., Tint, G.S., Hauser, S. J. Clin. Invest. (1988) [Pubmed]
  15. Bile acids and cytokines inhibit the human cholesterol 7 alpha-hydroxylase gene via the JNK/c-jun pathway in human liver cells. Li, T., Jahan, A., Chiang, J.Y. Hepatology (2006) [Pubmed]
  16. Functional inhibitory cross-talk between constitutive androstane receptor and hepatic nuclear factor-4 in hepatic lipid/glucose metabolism is mediated by competition for binding to the DR1 motif and to the common coactivators, GRIP-1 and PGC-1alpha. Miao, J., Fang, S., Bae, Y., Kemper, J.K. J. Biol. Chem. (2006) [Pubmed]
  17. Differential regulation of rat and human CYP7A1 by the nuclear oxysterol receptor liver X receptor-alpha. Goodwin, B., Watson, M.A., Kim, H., Miao, J., Kemper, J.K., Kliewer, S.A. Mol. Endocrinol. (2003) [Pubmed]
  18. Effect of increasing the expression of cholesterol transporters (StAR, MLN64, and SCP-2) on bile acid synthesis. Ren, S., Hylemon, P., Marques, D., Hall, E., Redford, K., Gil, G., Pandak, W.M. J. Lipid Res. (2004) [Pubmed]
  19. Effects of CYP7A1 overexpression on cholesterol and bile acid homeostasis. Pandak, W.M., Schwarz, C., Hylemon, P.B., Mallonee, D., Valerie, K., Heuman, D.M., Fisher, R.A., Redford, K., Vlahcevic, Z.R. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  20. A Prospero-related homeodomain protein is a novel co-regulator of hepatocyte nuclear factor 4alpha that regulates the cholesterol 7alpha-hydroxylase gene. Song, K.H., Li, T., Chiang, J.Y. J. Biol. Chem. (2006) [Pubmed]
  21. Feedback regulation of bile acid synthesis in primary human hepatocytes: evidence that CDCA is the strongest inhibitor. Ellis, E., Axelson, M., Abrahamsson, A., Eggertsen, G., Thörne, A., Nowak, G., Ericzon, B.G., Björkhem, I., Einarsson, C. Hepatology (2003) [Pubmed]
  22. Differences in the regulation of the classical and the alternative pathway for bile acid synthesis in human liver. No coordinate regulation of CYP7A1 and CYP27A1. Björkhem, I., Araya, Z., Rudling, M., Angelin, B., Einarsson, C., Wikvall, K. J. Biol. Chem. (2002) [Pubmed]
  23. Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis. Honda, A., Salen, G., Matsuzaki, Y., Batta, A.K., Xu, G., Hirayama, T., Tint, G.S., Doy, M., Shefer, S. J. Lipid Res. (2005) [Pubmed]
  24. Identification and characterization of cis-acting elements conferring insulin responsiveness on hamster cholesterol 7alpha-hydroxylase gene promoter. De Fabiani, E., Crestani, M., Marrapodi, M., Pinelli, A., Golfieri, V., Galli, G. Biochem. J. (2000) [Pubmed]
  25. Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7 alpha-hydroxylase gene transcription. Li, T., Chiang, J.Y. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  26. Regulation of cholesterol-7alpha-hydroxylase: BAREly missing a SHP. Davis, R.A., Miyake, J.H., Hui, T.Y., Spann, N.J. J. Lipid Res. (2002) [Pubmed]
  27. Farnesoid X receptor responds to bile acids and represses cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription. Chiang, J.Y., Kimmel, R., Weinberger, C., Stroup, D. J. Biol. Chem. (2000) [Pubmed]
  28. Xol INXS: role of the liver X and the farnesol X receptors. Fayard, E., Schoonjans, K., Auwerx, J. Curr. Opin. Lipidol. (2001) [Pubmed]
  29. Peroxisome proliferator-activated receptor alpha (PPARalpha) and agonist inhibit cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription. Marrapodi, M., Chiang, J.Y. J. Lipid Res. (2000) [Pubmed]
  30. Expression of key enzymes in bile acid biosynthesis during development: CYP7B1-mediated activities show tissue-specific differences. Norlin, M. J. Lipid Res. (2002) [Pubmed]
  31. A promoter polymorphism in cholesterol 7alpha-hydroxylase interacts with apolipoprotein E genotype in the LDL-lowering response to atorvastatin. Kajinami, K., Brousseau, M.E., Ordovas, J.M., Schaefer, E.J. Atherosclerosis (2005) [Pubmed]
  32. Interactions between common genetic polymorphisms in ABCG5/G8 and CYP7A1 on LDL cholesterol-lowering response to atorvastatin. Kajinami, K., Brousseau, M.E., Ordovas, J.M., Schaefer, E.J. Atherosclerosis (2004) [Pubmed]
  33. Regulation of hepatic low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and cholesterol 7alpha-hydroxylase mRNAs in human liver. Rudling, M., Angelin, B., Ståhle, L., Reihnér, E., Sahlin, S., Olivecrona, H., Björkhem, I., Einarsson, C. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  34. Cholesterol binding to cytochrome P450 7A1, a key enzyme in bile acid biosynthesis. Mast, N., Graham, S.E., Andersson, U., Bjorkhem, I., Hill, C., Peterson, J., Pikuleva, I.A. Biochemistry (2005) [Pubmed]
  35. Correlation of farnesoid X receptor coactivator recruitment and cholesterol 7alpha-hydroxylase gene repression by bile acids. Bramlett, K.S., Yao, S., Burris, T.P. Mol. Genet. Metab. (2000) [Pubmed]
 
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