title: LXRβ activation increases intestinal cholesterol absorption, leading to an atherogenic lipoprotein profile.
abstract: OBJECTIVE
  Liver X receptors (LXRs) are essential for the regulation of intestinal cholesterol absorption. Because two isoforms exist, LXRα and LXRβ, with overlapping but not identical functions, we investigated whether LXRα and LXRβ exert different effects on intestinal cholesterol absorption.
  
  
  METHODS
  Wild-type (WT), LXRα(-/-) and LXRβ(-/-) mice were fed control diet, 0.2% cholesterol-enriched diet or 0.2% cholesterol-enriched diet plus the LXR agonist GW3965.
  
  
  RESULTS
  When fed a control diet, all three genotypes showed similar levels of cholesterol absorption. Of interest, a significant increase in cholesterol absorption was found in the LXRα(-/-) mice, but not in the WT or LXRβ(-/-) animals, when fed a diet enriched with 0.2% cholesterol or 0.2% cholesterol + GW3965. Reduced faecal neutral sterol excretion and a hydrophobic bile acid profile were also observed in LXRα(-/-) mice. Greater increases in the apolipoprotein (apo)B-containing lipoproteins in serum were seen in the LXRα(-/-) mice. A 0.2% cholesterol +GW3965 diet suppressed intestinal Npc1l1 protein expression to the same extent for all genotypes, while Abca1 and Abcg5 were elevated to the same degree.
  
  
  CONCLUSIONS
  In the intestine, LXRα and LXRβ seem to exert similar effects on expression of cholesterol-transporting proteins such as Npc1l1. Selective activation of LXRβ may generate effects such as increased cholesterol absorption and elevated serum levels of apoB-containing lipoproteins, which seem to be counteracted by LXRα. Therefore, an intestinal LXRβ-specific pathway might exist in terms of cholesterol transportation in addition to the main pathway.
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden.
authors.forename: X
authors.initials: X
authors.lastname: Hu
authors.forename: K R
authors.initials: KR
authors.lastname: Steffensen
authors.forename: Z-Y
authors.initials: ZY
authors.lastname: Jiang
authors.forename: P
authors.initials: P
authors.lastname: Parini
authors.forename: J-Å
authors.initials: JÅ
authors.lastname: Gustafsson
authors.forename: M
authors.initials: M
authors.lastname: Gåfvels
authors.forename: G
authors.initials: G
authors.lastname: Eggertsen
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D001565:Benzoates / Q000008:administration & dosage; D001596:Benzylamines / Q000008:administration & dosage; D001646:Bile / Q000378:metabolism; D002784:Cholesterol / Q000097:blood*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods
chemical_list: C462600:ABCG5 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters; D001565:Benzoates; D001596:Benzylamines; D002791:Cholesterol, Dietary; C473027:GW 3965; D008074:Lipoproteins; D000071518:Liver X Receptors; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D012333:RNA, Messenger; D002784:Cholesterol