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Increasing dietary cholesterol induces different regulation of classic and alternative bile acid synthesis
Guorong Xu, … , Thomas S. Chen, David Greenblatt
Guorong Xu, … , Thomas S. Chen, David Greenblatt
Published January 1, 1999
Citation Information: J Clin Invest. 1999;103(1):89-95. https://doi.org/10.1172/JCI4414.
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Article

Increasing dietary cholesterol induces different regulation of classic and alternative bile acid synthesis

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Abstract

We investigated the effect of increasing dietary cholesterol on bile acid pool sizes and the regulation of the two bile acid synthetic pathways (classic, via cholesterol 7α-hydroxylase, and alternative, via sterol 27-hydroxylase) in New Zealand white rabbits fed 3 g cholesterol/per day for up to 15 days. Feeding cholesterol for one day increased hepatic cholesterol 75% and cholesterol 7α-hydroxylase activity 1.6 times without significant change of bile acid pool size or sterol 27-hydroxylase activity. After three days of cholesterol feeding, the bile acid pool size increased 83% (P < 0.01), and further feeding produced 10%–20% increments, whereas cholesterol 7α-hydroxylase activity declined progressively to 60% below baseline. In contrast, sterol 27-hydroxylase activity rose 58% after three days of cholesterol feeding and remained elevated with continued intake. Bile drainage depleted the bile acid pool and stimulated downregulated cholesterol 7α-hydroxylase activity but did not affect sterol 27-hydroxylase activity. Thus, increasing hepatic cholesterol does not directly inhibit cholesterol 7α-hydroxylase and initially favors enzyme induction, whereas increased bile acid pool is the most powerful inhibitor of cholesterol 7α-hydroxylase. Sterol 27-hydroxylase is insensitive to the bile acid flux but is upregulated by increasing hepatic cholesterol.

Authors

Guorong Xu, Gerald Salen, Sarah Shefer, G. Stephen Tint, Lien B. Nguyen, Thomas S. Chen, David Greenblatt

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Figure 1

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Flow diagram illustrating two pathways for bile acid synthesis. Choleste...
Flow diagram illustrating two pathways for bile acid synthesis. Cholesterol serves as the sole substrate and is converted to cholic acid via both classic and alternative pathways. Microsomal cholesterol 7α-hydroxylase is the initial and rate-controlling enzyme for the classic pathway, whereas mitochondrial sterol 27-hydroxylase initiates the alternative pathway and might be rate limiting. The product, 27-hydroxycholesterol, is then 7α-hydroxylated by microsomal oxysterol 7α-hydroxylase (27-hydroxycholesterol–7α-hydroxylase), which is different from microsomal cholesterol 7α-hydroxylase.

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