Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in mice.
OBJECTIVE
Reverse cholesterol transport (RCT) is defined as high-density lipoprotein (HDL)-mediated flux of excess cholesterol from peripheral cells to liver, followed by secretion into bile and disposal via the feces. Various steps of this pathway are controlled by the liver X receptor (LXR). We addressed the role of the intestine in LXR-dependent stimulation of fecal cholesterol excretion.


METHODS
To segregate biliary from intestine-derived cholesterol, wild-type and Mdr2 P-glycoprotein-deficient mice ( Mdr2 -/- ), which are unable to secrete cholesterol into bile, were treated with the LXR agonist GW3965.


RESULTS
Treatment with GW3965 increased biliary cholesterol secretion by 74% in wild-type mice but had no effect in Mdr2 -/- mice. LXR activation increased fecal neutral sterol excretion 2.1-fold in wild-type mice. Surprisingly, an identical increase was observed in Mdr2 -/- mice. Fractional cholesterol absorption was reduced on LXR activation in both strains but was more pronounced in Mdr2 -/- mice, coinciding with reduced Npc111 expression. Intestinal gene expression of ATP-binding cassette transporters (Abc) Abca1 , Abcg1 , Abcg5 , and Abcg8 was strongly induced upon LXR activation in both strains, whereas expression of HMGCoA reductase , controlling cholesterol synthesis, remained unaffected. Additionally, LXR activation stimulated the excretion of plasma-derived [ 3 H]cholesterol into the fecal neutral sterol fraction in Mdr2 -/- mice.


CONCLUSIONS
Increased fecal cholesterol loss upon LXR activation is independent of biliary cholesterol secretion in mice. An important part of excess cholesterol is excreted directly via the intestine, supporting the existence of an alternative, quantitatively important route for cholesterol disposal.
Kruit
Janine K
JK
Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. j.k.kruit@med.rug.nl
Plösch
Torsten
T
Havinga
Rick
R
Boverhof
Renze
R
Groot
Pieter H E
PH
Groen
Albert K
AK
Kuipers
Folkert
F
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts / Q000378:metabolism*; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005243:Feces / Q000737:chemistry*; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013261:Sterols; D002784:Cholesterol