Delineation of molecular changes in intrahepatic cholesterol metabolism resulting from diminished cholesterol absorption

Joyce J. Repa, Stephen D. Turley, Gang Quan, John M. Dietschy

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

The absorption of cholesterol by the small intestine is a major route for the net entry of cholesterol into the body and can therefore affect the plasma low density lipoprotein-cholesterol (LDL-C) concentration. These studies used ezetimibe, a potent inhibitor of cholesterol absorption, to delineate the biochemical and molecular changes in intrahepatic metabolism and biliary lipid secretion when there is a major reduction in chylomicron cholesterol delivery to the liver. In female LDL receptor (LDLR)-deficient (LDLR-/-) mice fed a basal diet containing ezetimibe (0-10 mg/day/ kg body weight), cholesterol absorption was reduced up to 91%, fecal neutral sterol excretion was increased up to 4.7-fold, and plasma total cholesterol concentrations decreased by up to 18%. Blocking cholesterol absorption prevented the accumulation of very low density lipoproteins and LDL in the circulation of LDLR-/- mice fed a lipid-rich diet. In female LDLR+/+ mice fed the lipid-rich diet with ezetimibe, the relative mRNA level for the LDLR in the liver was 2-fold greater than in matching mice given the lipid-rich diet alone. DD We conclude that in the mouse the reduction in plasma LDL-C levels induced by blocking cholesterol absorption reflects both a diminished rate of LDL-C production and a modest increase in hepatic LDLR expression.

Original languageEnglish (US)
Pages (from-to)779-789
Number of pages11
JournalJournal of lipid research
Volume46
Issue number4
DOIs
StatePublished - Dec 1 2005

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Keywords

  • Adenosine triphosphate binding cassette transporters
  • Apolipoprotein composition
  • Bile acid excretion
  • Biliary lipid composition
  • Cholesterol excretion
  • Cholesterol synthesis
  • Enterocyte
  • Hepatocyte
  • Liver X receptor

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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