Niemann-Pick C1-like 1 is required for an LXR agonist to raise plasma HDL cholesterol in mice.
OBJECTIVE
Activation of liver x receptor (LXR) raises plasma HDL-cholesterol (HDL-C) in mice. Interestingly, the LXR agonist GW3965 fails to raise plasma HDL-C in mice lacking intestinal ABCA1, indicating that intestinal ABCA1 plays a predominant role in GW3965-mediated HDL production. How this is coupled to intestinal function remains elusive. Because cholesterol is essential for HDL assembly and directly regulates intestinal ABCA1 expression via activating LXR, we hypothesized that cholesterol absorption, a major function of intestine, modulates LXR-dependent HDL formation.


RESULTS
Mice lacking Niemann-Pick C1-Like 1 (NPC1L1) (L1-KO mice), a gene that is essential for cholesterol absorption, were treated with LXR agonist T0901317 for 7 days. Intriguingly, this treatment failed to significantly raise plasma HDL-C but caused a much greater fecal cholesterol excretion in L1-KO mice. The intestinal ABCA1 mRNA level was about 4-fold lower in L1-KO versus wild-type mice, and increased 3.9-fold and 8.8-fold after T0901317 treatment in wild-type and L1-KO mice, respectively. Hepatic ABCA1 failed to respond to T0901317 in mice of both genotypes, although hepatic mRNAs for many LXR target genes were higher in the T0901317-treated versus untreated wild-type animals.


CONCLUSIONS
NPC1L1 is required for an LXR agonist to increase plasma HDL-C in mice.
Tang
Weiqing
W
Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040, USA.
Ma
Yinyan
Y
Jia
Lin
L
Ioannou
Yiannis A
YA
Davies
Joanna P
JP
Yu
Liqing
L
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D001774:Blood Chemical Analysis; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects* / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D007274:Injections, Intraperitoneal; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052556:Niemann-Pick Disease, Type C / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D057093:Orphan Nuclear Receptors; D011336:Probability; D011897:Random Allocation; D018160:Receptors, Cytoplasmic and Nuclear; D012680:Sensitivity and Specificity
D018528:ATP-Binding Cassette Transporters; D001565:Benzoates; D001596:Benzylamines; D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; C473027:GW 3965; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear