Regulation of cholesterol 7α-hydroxylation by cholesterol synthesis in rat liver

Abstract

Hepatic cholesterol 7α-hydroxylation and cholesterogenesis were determined in vitro at various time intervals 6 hr after oral or intravenous administration to fasted rats. Glucose administration to fasted rats enhanced cholesterol 7α-hydroxylation as well as fatty acid or cholesterol synthesis in the liver, though significant changes were not demonstrated in the cholesterol content of liver and serum throughout the observed periods. Hepatic cholesterol synthesis increased 1 hr after oral glucose ingestion. On the other hand, cholesterol 7α-hydroxylation was stimulated 2 hr after oral glucose administration, with a lag phase of 1 hr following the induction of cholesterol synthesis. From the results of the experiments on the effect of glucose ingestion, it appeared that cholesterol 7α-hydroxylation was correlated with hepatic cholesterogenesis. Hepatic cholesterogenesis was decreased in triparanol-treated rats and was not stimulated by glucose administration. Triparanol did not affect cholesterol hydroxylation in the fasted state, but did abolish the stimulatory effect of glucose. Short-term feeding of a high-cholesterol diet, which suppressed hepatic cholesterol synthesis, stimulated cholesterol 7α-hydroxylation. Oral administration of glucose to cholesterol-fed rats still further accelerated hydroxylation. In rats with ligated bile ducts, hepatic cholesterogenesis increased 24 hr after bileduct ligation while hydroxylation decreased 24 hr after the operation but was stimulated after 72 hr. Glucose ingestion by these rats stimulated both cholesterol synthesis and hydroxylation. It is concluded that increased hepatic cholesterogenesis enhances cholesterol 7α-hydroxylase activity; this activity does not depend upon increased fatty acid or other lipid synthesis, altered bile flow or gastrointestinal factors. Increased dietary cholesterol intake also accelerates hydroxylase activity. These mechanisms may preserve homeostasis in the serum cholesterol level, and an altered balance between these two enzyme systems — anabolic and catabolic — probably induces a change in the size of the body cholesterol pool.