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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:448.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Niemann-Pick C1-Like 1 Is Required for an LXR Agonist to Raise Plasma HDL Cholesterol in Mice

Weiqing Tang; Yinyan Ma; Lin Jia; Yiannis A. Ioannou; Joanna P. Davies; Liqing Yu

From the Department of Pathology Section on Lipid Sciences (W.T., Y.M., L.J., L.Y.), Wake Forest University School of Medicine, Winston-Salem, North Carolina; and the Department of Human Genetics (Y.A.I., J.P.D.), Mount Sinai School of Medicine, New York.

Correspondence to Liqing Yu, MD, PhD, Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040. E-mail lyu{at}wfubmc.edu

Objectives— 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.

Methods and 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.

T0901317 increased fecal cholesterol excretion but failed to raise plasma HDL cholesterol in mice lacking NPC1L1. Because NPC1L1 is essential for cholesterol absorption and exclusively expressed in intestine in mice, this finding suggests that intestinal cholesterol absorption is required for an LXR agonist to raise plasma HDL cholesterol in mice.

Key Words: cholesterol absorption • Niemann-Pick C1-Like 1 • liver x receptor • HDL • ABCA1

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