Transintestinal Cholesterol Transport Is Active in Mice and Humans and Controls Ezetimibe-Induced Fecal Neutral Sterol Excretion

Lily Jakulj, Theo H van Dijk, Jan Freark de Boer, Ruud S Kootte, Marleen Schonewille, Yared Paalvast, Theo Boer, Vincent W Bloks, Renze Boverhof, Max Nieuwdorp, Ulrich H W Beuers, Erik S G Stroes, Albert K Groen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Except for conversion to bile salts, there is no major cholesterol degradation pathway in mammals. Efficient excretion from the body is therefore a crucial element in cholesterol homeostasis. Yet, the existence and importance of cholesterol degradation pathways in humans is a matter of debate. We quantified cholesterol fluxes in 15 male volunteers using a cholesterol balance approach. Ten participants repeated the protocol after 4 weeks of treatment with ezetimibe, an inhibitor of intestinal and biliary cholesterol absorption. Under basal conditions, about 65% of daily fecal neutral sterol excretion was bile derived, with the remainder being contributed by direct transintestinal cholesterol excretion (TICE). Surprisingly, ezetimibe induced a 4-fold increase in cholesterol elimination via TICE. Mouse studies revealed that most of ezetimibe-induced TICE flux is mediated by the cholesterol transporter Abcg5/Abcg8. In conclusion, TICE is active in humans and may serve as a novel target to stimulate cholesterol elimination in patients at risk for cardiovascular disease.

Original languageEnglish
Pages (from-to)783-794
Number of pages12
JournalCell Metabolism
Volume24
Issue number6
DOIs
Publication statusPublished - 13 Dec 2016

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