title: Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1.
abstract: The ATP-binding cassette transporter ABCA1 is essential for high density lipoprotein (HDL) formation and considered rate-controlling for reverse cholesterol transport. Expression of the Abca1 gene is under control of the liver X receptor (LXR). We have evaluated effects of LXR activation by the synthetic agonist T0901317 on hepatic and intestinal cholesterol metabolism in C57BL/6J and DBA/1 wild-type mice and in ABCA1-deficient DBA/1 mice. In wild-type mice, T0901317 increased expression of Abca1 in liver and intestine, which was associated with an approximately 60% rise in HDL. Biliary cholesterol excretion rose 2.7-fold upon treatment, and fecal neutral sterol output was increased by 150-300%. Plasma cholesterol levels also increased in treated Abca1(-/-) mice (+120%), but exclusively in very low density lipoprotein-sized fractions. Despite the absence of HDL, hepatobiliary cholesterol output was stimulated upon LXR activation in Abca1(-/-) mice, leading to a 250% increase in the biliary cholesterol/phospholipid ratio. Most importantly, fecal neutral sterol loss was induced to a similar extent (+300%) by the LXR agonist in DBA/1 wild-type and Abca1(-/-) mice. Expression of Abcg5 and Abcg8, recently implicated in biliary excretion of cholesterol and its intestinal absorption, was induced in T0901317-treated mice. Thus, activation of LXR in mice leads to enhanced hepatobiliary cholesterol secretion and fecal neutral sterol loss independent of (ABCA1-mediated) elevation of HDL and the presence of ABCA1 in liver and intestine.
authors.affiliation: Center for Liver, Digestive, and Metabolic Diseases, Groningen University Institute for Drug Exploration, Department of Pediatrics, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. t.ploesch@med.rug.nl
authors.forename: Torsten
authors.initials: T
authors.lastname: Plōsch
authors.forename: Tineke
authors.initials: T
authors.lastname: Kok
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Bloks
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Smit
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chimini
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001646:Bile / Q000378:metabolism*; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005234:Fatty Liver / Q000209:etiology; D005243:Feces / Q000737:chemistry*; D006845:Hydrocarbons, Fluorinated; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000502:physiology*; D013449:Sulfonamides; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000924:Anticholesteremic Agents; D002784:Cholesterol; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides