ACAT2 deficiency limits cholesterol absorption in the cholesterol-fed mouse: Impact on hepatic cholesterol homeostasis

Joyce J. Repa, Kimberly K. Buhman, Robert V. Farese, John M. Dietschy, Stephen D. Turley

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

Acyl CoA:cholesterol acyltransferase (ACAT) 2 is the major cholesterol-esterifying enzyme in mouse enterocytes and hepatocytes. Male ACAT2+/+ and ACAT2-/- mice were fed chow containing added cholesterol (0%-0.500% w/w) for 24 days. Over this range, fractional cholesterol absorption in the ACAT2+/+ mice fell from 41.4% ± 6.6% to 21.0% ± 5.2%, and in their ACAT2-/- counterparts it fell from 35.1% ± 4.5% to 7.9% ± 0.8%. The mass of dietary cholesterol absorbed (mg/d per 100 g body weight) increased from 1.2 ± 0.2 to 14.7 ± 4.4 in the ACAT2+/+ mice and from 1.0 ± 0.2 to 5.5 ± 0.6 in those without ACAT2. In the ACAT2+/+ mice, hepatic cholesterol concentrations increased as a function of intake despite compensatory changes in cholesterol and bile acid synthesis and in the expression of adenosine triphosphate-binding cassette transporter G5 (ABCG5) and ABC transporter G8 (ABCG8). In contrast, in ACAT2-/- mice in which the amount of cholesterol absorbed at the highest intake was only 37% of that in the ACAT2+/+ mice, suppression of synthesis was a sufficient adaptive response; there was no change in bile acid synthesis, ABCG5/G8 expression, or hepatic cholesterol concentration. The expression of adenosine triphosphate - binding cassette transporter A1 (ABCA1) in the jejunum was markedly elevated in the ACAT2-/- mice, irrespective of dietary cholesterol level. In conclusion, although ACAT2 deficiency limits cholesterol absorption, the extent to which it impacts hepatic cholesterol homeostasis depends on cholesterol intake. Loss of ACAT2 activity may result in unesterified cholesterol being absorbed via an ABCA1-mediated basolateral efflux pathway.

Original languageEnglish (US)
Pages (from-to)1088-1097
Number of pages10
JournalHepatology
Volume40
Issue number5
DOIs
StatePublished - Nov 2004

ASJC Scopus subject areas

  • Hepatology

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