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(Circulation. 2006;113:90-97.)
© 2006 American Heart Association, Inc.

Vascular Medicine

Pharmacological Activation of Liver X Receptors Promotes Reverse Cholesterol Transport In Vivo

Snehal U. Naik, PhD; Xun Wang, PhD; Jaqueline S. Da Silva, PhD; Michael Jaye, PhD; Colin H. Macphee, PhD; Muredach P. Reilly, MD; Jeffrey T. Billheimer, PhD; George H. Rothblat, PhD; Daniel J. Rader, MD

From the Institute for Translational Medicine and Therapeutics (S.U.N., X.W., M.P.R., J.T.B., D.J.R.), Cardiovascular Institute (M.P.R., D.J.R.), and Institute for Diabetes Obesity and Metabolism (M.P.R., D.J.R.), University of Pennsylvania School of Medicine, Philadelphia; The Children’s Hospital of Philadelphia, Philadelphia, Pa (J.S.D., G.H.R.); and GlaxoSmithKline, King of Prussia, Pa (M.J., C.H.M.).

Correspondence to Daniel J. Rader, MD, University of Pennsylvania Medical Center, 654 Biomedical Research Building II/III, 421 Curie Blvd, Philadelphia PA 19104. E-mail rader{at}mail.med.upenn.edu

Received May 5, 2005; revision received August 25, 2005; accepted September 12, 2005

Background— Liver X receptors (LXRs) are ligand-activated transcription factors involved in the control of lipid metabolism and inflammation. Synthetic LXR agonists have been shown to inhibit the progression of atherosclerosis in mice, but the mechanism is uncertain. LXR agonism upregulates the genes encoding ATP binding cassette transporters A1 (ABCA1) and G1 (ABCG1) in macrophages, thus promoting efflux of cholesterol; it also upregulates liver and intestinal ABCG5 and ABCG8, helping to promote biliary and fecal excretion of cholesterol. Thus, LXR agonism may inhibit atherosclerosis through promotion of reverse cholesterol transport (RCT) in vivo, but this has not been proven. We previously described an in vivo method to trace the movement of cholesterol from ³H-cholesterol–labeled J774 macrophages into plasma, into liver, and ultimately into the bile and feces as free cholesterol or bile acids. In the present study we used this approach to test the hypothesis that administration of the synthetic LXR agonist GW3965 would increase the rate of macrophage RCT in vivo.

Methods and Results— Three different mouse models—wild-type C57BL/6 mice, LDLR/apobec-1 double knockout mice, and human apolipoprotein (apo)B/cholesteryl ester transfer protein (CETP) double transgenic mice—were treated with either vehicle or GW3965. Mice were injected intraperitoneally with ³H-cholesterol–labeled and cholesterol-loaded macrophages and monitored for the appearance of ³H-tracer in plasma, liver, and feces. Administration of GW3965 significantly increased the levels of ³H-tracer in plasma and feces in all 3 mouse models.

Conclusions— These results demonstrate that administration of the LXR agonist GW3965 increases the rate of RCT from macrophages to feces in vivo.

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