Abstract
To study the molecular mechanism of regulation of cholesterol 7α-hydroxylase, the rate-limiting enzyme in bile acid synthesis, we have purified a rat liver cholesterol 7α-hydroxylase, obtained a specific antibody, cloned the cDNA and expressed an active enzyme in E. Coli. Using these reagents, we studied the regulation of 7α-hydroxylase by cholesterol, oxysterols, bile acids, hormones and other drugs. All results indicate that 7α-hydroxylase is regulated at the gene transcriptional level. The human cholesterol 7α-hydroxylase cDNA was cloned and polymorphisms were identified in a human liver. The rat 7α-hydroxylase gene was cloned and several liver specific and ubiquitous regulatory elements were found in the 5’-upstream sequence of the rat gene. Possible mechanisms of regulation of 7α-hydroxylase are proposed.
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References
Myant, N.B. and Mitropoulos, K.A. (1979) “Cholesterol 7α-hydroxylase.” J. Lipid Res. 18, 135–153.
Chiang, J.Y.L., Miller, W.F. and Lin, G.-M. (1990) “Regulation of cholesterol 7α-hydroxylase:Purification of cholesterol 7α-hydroxylase and the immunochemical evidence for the induction of cholesterol 7α-hydroxylase by cholestyramine and circadian rhythm.” J. Biol. Chem. 265, 3889–3897.
Ogishima T., Deguchi, S. and Okuda, K. (1987) “Purification and characterization of cholesterol 7α-hydroxylase from rat liver microsomes.” J. Biol. Chem. 262, 7646–7650.
Li, Y.C., Wang, D.P. and Chiang, J.Y.L. (1990) “Regulation of cholesterol 7α-hydroxylase in the liver: cDNA cloning, sequencing and regulation of cholesterol 7α-hydroxylase mRNA.” J. Biol. Chem. 265, 12012–12019.
Jelinek, D. F., Andersson S., Slaughter, C.A. and Russell, D. W. (1990) “Cloning and regulation of cholesterol 7α-hydroxylasen, the rate-limiting enzyme in bile acid biosynthesis.” J. Biol. Chem. 265, 8190–8197.
Pandak, W. M., Li, Y.C., Chiang, J.Y.L., Studer, E.J., Gurley, E.C., Heuman, D.M., Vlahcevic, Z. R. and Hylemon, P.B. (1991) “Regulation of cholesterol 7α-hydroxylase mRNA and transcriptional activity by taurocholate and cholesterol in the chronic biliary diverted rat.” J. Biol. Chem. 266, 3416–3421.
Duckworth, P.F., Vlahcevic, Z.R., Studer, E.J., Gurley, E.C., Heuman, D.M., Beg, Z.H. and Hylemon, P.B. (1991) “Effect of hydrophobic bile acids on HMG-CoA reductase activity and mRNA levels in the rat.” J. Biol. Chem. 266, 9413–9418.
Ness, G.C., Keller, R.K., and Pendleton, L.C. (1991) “Feedback regulation of hepatic HMG-CoA reductase activity by dietary cholesterol is not due to altered mRNA levels.” J. Biol. Chem. 266, 14854–14857.
Clark, C.F., Fogelman, A.M. and Edwards, P.A. (1985) “Transcriptional regulation of the HMG-CoA reductase gene in rat liver.” J. Biol. Chem. 260, 14363–14367.
Clark, C.F., Edwards, P.A., Lan, S.F., Tanaka, R.D. and Fogelman, A.M. (1983) “Regulation of HMG-CoA reductase mRNA levels in rat liver.” J. Biol. Chem. Proc. Natl. Acad. Sci. 80, 3305–3308.
Ness, G.C., Pendleton, L.C., Li, Y.C. and Chiang, J.Y.L. (1991) “Effect of thyroid hormone on hepatic cholesterol 7α-hydroxylase, LDL receptor, HMG-CoA reductase, farnesyl pyrophosphate synthetase and apolipoprotein A-l mRNA levels in hypophysectomized rats.” Biochem. biophys. Res. Commun. 172, 1150–1156.
Leighton, J.K., Dueland S., Straka, M.S., Trawick, J. and Davis, R.A. (1991) “Activation of the silent endogenous cholesterol 7α-hydroxylase gene in rat hepatoma cells: — new complementation group having resistance to 25-hydroxycholesterol.” Mol. Cell. Biol. 11, 2049–2056.
Princen, H.N.G., Meijer, P., and Hoffee, B. (1989) “Dexamethasone regulates bile acid synthesis in monolayer cultures of rat hepatocytes by induction of cholesterol 7α-hydroxylase.” Biochem. J. 262, 341–348.
Simonet, W.S. and Ness, G.C. (1989) “Post-transcriptional regulation of HMG-CoA reductase mRNA in rat liver.” J. Biol. Chem. 264, 569–573.
Tang, P.M., Finkelstein, J.A., and Chiang, J.Y.L. (1988) “Expression of hepatic microsomal cholesterol 7α-hydroxylase activity in lean and obese Zucker rats.” Biochem. Biophys. Res. Commun. 150, 853–858.
Noshiro, M., Nishimoto, M. and Okuda, K. (1990) “Rat liver cholesterol 7α-hydroxylase. Pretranslational regulation for circadian rhythm.” J. Biol. Chem. 265, 10036–10041.
Li, Y.C. and Chiang, J.Y.L. (1992) “The expression of — catalytically active cholesterol 7α-hydroxylase cytochrome P450 in E. coli.” J. Biol. Chem. 266, 19186–19191.
Breuer O., Sudjana-Sugiaman, E., Eggertsen G., Chiang, J.Y.L. and Bjorkhem, I. (1992) “Cholesterol 7α-hydroxylase is upregulated by the competitive inhibitor 7-oxocholesterol in rat liver.” Submitted.
Karam, W.G. and Chiang, J.Y.L. (1992) “Polymorphisms of human cholesterol 7α-hydroxylase (CYP7).” Biochem. Biophys. Res. Commun. In press.
Noshiro, M. and Okuda, K. (1990) “Molecular cloning and seguence analysis of cDNA encoding human cholesterol 7α-hydroxylase.” FEBS Lett. 268, 137–140.
Jelinek, D.F. and Russell, D.W. (1990) “Structure of the rat gene encoding cholesterol 7α-hydroxylase.” Biochem. 29, 7781–7785.
Nishimoto, M., Gotoh, O., Okuda, K. and Noshiro, M. (1991) “Structural analysis of the gene encoding rat cholesterol 7α-hydroxylase, the key enzyme for bile acid biosynthesis.” J. Biol. Chem. 266, 6467–6471.
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Karam, W.G., Yang, T.P., Wang, D.P., Chiang, J.Y.L. (1993). The Expression and Regulation of Cholesterol 7α-Hydroxylase. In: Catapano, A.L., Gotto, A.M., Smith, L.C., Paoletti, R. (eds) Drugs Affecting Lipid Metabolism. Medical Science Symposia Series, vol 2. Springer, Dordrecht. https://doi.org/10.1007/978-94-011-1703-6_18
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DOI: https://doi.org/10.1007/978-94-011-1703-6_18
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