title: Liver X receptor agonist modulation of cholesterol efflux in mice with intestine-specific deletion of microsomal triglyceride transfer protein.
abstract: OBJECTIVE
  Previous work demonstrated that intestinal cholesterol absorption and regulated expression of intestinal Niemann-Pick C1-like 1 and ATP-binding cassette protein A1 are required for liver X receptor (LXR) agonist-mediated increases in high-density lipoprotein biogenesis. We re-examined those conclusions in mice with intestine-specific deletion of the microsomal triglyceride transfer protein (MTTP-IKO), where chylomicron formation is eliminated.
  
  
  RESULTS
  MTTP-IKO mice demonstrated sustained ≈90% reduction in cholesterol absorption and >80% reduction in Niemann-Pick C1-like 1 expression, yet LXR agonist treatment increased serum high-density lipoprotein and upregulated intestinal ATP-binding cassette protein A1 expression. Hepatic lipogenesis and triglyceride content increased with LXR agonist treatment in both genotypes. Biliary cholesterol secretion was increased in MTTP-IKO mice without further increase upon LXR agonist administration. LXR agonist treatment caused a paradoxical increase in cholesterol absorption in MTTP-IKO mice and decreased fecal neutral sterol excretion, but to levels that still exceeded fecal neutral sterol excretion in LXR agonist-treated control mice. Finally, MTTP-IKO mice demonstrated indistinguishable patterns of increased cholesterol turnover and efflux after intravenous radiolabeled cholesterol administration, with or without LXR agonist treatment.
  
  
  CONCLUSIONS
  Both intestinal and hepatic cholesterol efflux pathways are basally upregulated in MTTP-IKO mice. Moreover, LXR-dependent pathways modulate intestinal cholesterol absorption, transport, efflux, and high-density lipoprotein production independent of chylomicron assembly and secretion.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xie
authors.forename: Susan
authors.initials: S
authors.lastname: Kennedy
authors.forename: Rohini
authors.initials: R
authors.lastname: Sidhu
authors.forename: Jianyang
authors.initials: J
authors.lastname: Luo
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.forename: Nicholas O
authors.initials: NO
authors.lastname: Davidson
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D005243:Feces / Q000737:chemistry; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D008076:Cholesterol, HDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol