Original Article

Regulation of classic and alternative bile acid synthesis in hypercholesterolemic rabbits: effects of cholesterol feeding and bile acid depletion

Correspondence to: Gerald Salen.

The effect of cholesterol feeding (3 g/day) on bile acid synthesis was examined in 10 New Zealand white rabbits (NZW), 8 Watanabe heterozygous and 10 homozygous rabbits with partial and complete deficiencies of LDL receptors. After 10 days of cholesterol feeding, bile fistulas were constructed and bile acid pool sizes were measured. Cholesterol feeding increased plasma and hepatic cholesterol levels in all rabbit groups. Baseline bile acid pool sizes were smaller (P < 0.01) in heterozygotes (139 ± 3 mg) and homozygotes (124 ± 30 mg) than NZW rabbits (254 ± 44 mg). After feeding cholesterol, bile acid pool sizes doubled with increased cholic acid synthesis in NZW and, to a lesser extent, in Watanabe heterozygous rabbits but not in homozygotes. Baseline cholesterol 7-hydroxylase activity in NZW and heterozygotes declined 69% and 53% (P < 0.001), respectively, after cholesterol feeding. Sterol 27-hydroxylase activity reflecting alternative bile acid synthesis increased 66% (P < 0.01) in NZW and 37% in Watanabe heterozygotes but not in homozygotes after feeding cholesterol. Bile fistula drainage stimulated cholesterol 7-hydroxylase activity but not sterol 27-hydroxylase activity in all three rabbit groups.

These results demonstrated that dietary cholesterol increased hepatic sterol 27-hydroxylase activity and alternative bile acid synthesis to expand the bile acid pool and inhibited cholesterol 7-hydroxylase in NZW and in Watanabe heterozygous rabbits but not in homozygotes with absent hepatic LDL receptor function. Thus, in rabbits, sterol 27-hydroxylase is up-regulated by the increased hepatic cholesterol that enters the liver via LDL receptors whereas cholesterol 7-hydroxylase is controlled by the circulating hepatic bile acid flux.—Xu, G., G. Salen, S. Shefer, G. S. Tint, L. B. Nguyen, T. T. Parker, T. S. Chen, J. Roberts, X. Kong, and D. Greenblatt. Regulation of classic and alternative bile acid synthesis in hypercholesterolemic rabbits: effects of cholesterol feeding and bile acid depletion. J. Lipid Res. 1998. 39: 1608–1615.

Supplementary key words: LDL receptor, bile fistula, cholesterol 7-hydroxylase, cholic acid, HMG-CoA reductase

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. Otte, H. Kranz, I. Kober, P. Thompson, M. Hoefer, B. Haubold, B. Remmel, H. Voss, C. Kaiser, M. Albers, et al. Identification of Farnesoid X Receptor {beta} as a Novel Mammalian Nuclear Receptor Sensing Lanosterol Mol. Cell. Biol., February 1, 2003; 23(3): 864 - 872. [Abstract] [Full Text]

				J. Y. Chen, B. Levy-Wilson, S. Goodart, and A. D. Cooper Mice Expressing the Human CYP7A1 Gene in the Mouse CYP7A1 Knock-out Background Lack Induction of CYP7A1 Expression by Cholesterol Feeding and Have Increased Hypercholesterolemia When Fed a High Fat Diet J. Biol. Chem., November 1, 2002; 277(45): 42588 - 42595. [Abstract] [Full Text] [PDF]

				J. G. Menke, K. L. Macnaul, N. S. Hayes, J. Baffic, Y.-S. Chao, A. Elbrecht, L. J. Kelly, M.-H. Lam, A. Schmidt, S. Sahoo, et al. A Novel Liver X Receptor Agonist Establishes Species Differences in the Regulation of Cholesterol 7{alpha}-Hydroxylase (CYP7a) Endocrinology, July 1, 2002; 143(7): 2548 - 2558. [Abstract] [Full Text] [PDF]

				M. Norlin Expression of key enzymes in bile acid biosynthesis during development: CYP7B1-mediated activities show tissue-specific differences J. Lipid Res., May 1, 2002; 43(5): 721 - 731. [Abstract] [Full Text] [PDF]

				M. Souidi, M. Combettes-Souverain, F. Milliat, E. R. Eckhardt, O. Audas, S. Dubrac, M. Parquet, J. Férézou, and C. Lutton Hamsters Predisposed to Sucrose-Induced Cholesterol Gallstones (LPN Strain) Are More Resistant to Excess Dietary Cholesterol than Hamsters That Are Not Sensitive to Cholelithiasis Induction J. Nutr., June 1, 2001; 131(6): 1803 - 1811. [Abstract] [Full Text]

				A. Honda, G. Salen, S. Shefer, Y. Matsuzaki, G. Xu, A. K. Batta, G. S. Tint, and N. Tanaka Regulation of 25- and 27-hydroxylation side chain cleavage pathways for cholic acid biosynthesis in humans, rabbits, and mice: assay of enzyme activities by high-resolution gas chromatography;-mass spectrometry J. Lipid Res., March 1, 2000; 41(3): 442 - 451. [Abstract] [Full Text]

				G. J. Schroepfer Jr. Oxysterols: Modulators of Cholesterol Metabolism and Other Processes Physiol Rev, January 1, 2000; 80(1): 361 - 554. [Abstract] [Full Text] [PDF]