Activation of the liver X receptor stimulates trans-intestinal excretion of plasma cholesterol.
Recent studies have indicated that direct intestinal secretion of plasma cholesterol significantly contributes to fecal neutral sterol loss in mice. The physiological relevance of this novel route, which represents a part of the reverse cholesterol transport pathway, has not been directly established in vivo as yet. We have developed a method to quantify the fractional and absolute contributions of several cholesterol fluxes to total fecal neutral sterol loss in vivo in mice, by assessing the kinetics of orally and intravenously administered stable isotopically labeled cholesterol combined with an isotopic approach to assess the fate of de novo synthesized cholesterol. Our results show that trans-intestinal cholesterol excretion significantly contributes to removal of blood-derived free cholesterol in C57Bl6/J mice (33% of 231 micromol/kg/day) and that pharmacological activation of LXR with T0901317 strongly stimulates this pathway (63% of 706 micromol/kg/day). Trans-intestinal cholesterol excretion is impaired in mice lacking Abcg5 (-4%), suggesting that the cholesterol transporting Abcg5/Abcg8 heterodimer is involved in this pathway. Our data demonstrate that intestinal excretion represents a quantitatively important route for fecal removal of neutral sterols independent of biliary secretion in mice. This pathway is sensitive to pharmacological activation of the LXR system. These data support the concept that the intestine substantially contributes to reverse cholesterol transport.
Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.
Jelske N
JN
van der Veen
Theo H
TH
van Dijk
Carlos L J
CL
Vrins
Hester
H
van Meer
Rick
R
Havinga
Klaas
K
Bijsterveld
Uwe J F
UJ
Tietge
Albert K
AK
Groen
Folkert
F
Kuipers
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000819:agonists / Q000378:metabolism*; D004655:Emulsions / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D005243:Feces / Q000737:chemistry; D005260:Female; D015870:Gene Expression; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D007700:Kinetics; D008074:Lipoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013261:Sterols / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014018:Tissue Distribution; D014280:Triglycerides / Q000008:administration & dosage / Q000493:pharmacokinetics; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol; D004268:DNA-Binding Proteins; D004655:Emulsions; D006845:Hydrocarbons, Fluorinated; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013261:Sterols; D013449:Sulfonamides; D014280:Triglycerides; C462600:ABCG5 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides