Transintestinal Cholesterol Transport Is Active in Mice and Humans and Controls Ezetimibe-Induced Fecal Neutral Sterol Excretion.
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.
Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, the Netherlands.
Lily
L
Jakulj
Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen 9713ZG, the Netherlands.
Theo H
TH
van Dijk
Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713ZG, the Netherlands.
Jan Freark
JF
de Boer
Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, the Netherlands.
Ruud S
RS
Kootte
Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713ZG, the Netherlands.
Marleen
M
Schonewille
Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713ZG, the Netherlands.
Yared
Y
Paalvast
Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen 9713ZG, the Netherlands.
Theo
T
Boer
Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713ZG, the Netherlands.
Vincent W
VW
Bloks
Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen 9713ZG, the Netherlands.
Renze
R
Boverhof
Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, the Netherlands.
Max
M
Nieuwdorp
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam 1105AZ, the Netherlands.
Ulrich H W
UH
Beuers
Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, the Netherlands.
Erik S G
ES
Stroes
Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, the Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen 9713ZG, the Netherlands; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713ZG, the Netherlands; Amsterdam Diabetes Research Center, Academic Medical Center, Amsterdam 1105AZ, the Netherlands; Groningen Center of Systems Biology, University Medical Center Groningen, Groningen 9713ZG, the Netherlands. Electronic address: a.k.groen@amc.uva.nl.
Albert K
AK
Groen
D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8 / Q000172:deficiency / Q000378:metabolism; D000328:Adult; D000818:Animals; D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D000069438:Ezetimibe / Q000494:pharmacology*; D005243:Feces / Q000737:chemistry*; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D007700:Kinetics; D008074:Lipoproteins / Q000172:deficiency / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged
C462601:ABCG8 protein, mouse; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D001647:Bile Acids and Salts; D008074:Lipoproteins; D002784:Cholesterol; D000069438:Ezetimibe
bile salt; biliary cholesterol; reverse cholesterol transport; transintestinal cholesterol transport