Published online before print December 19, 2005, doi: 10.1161/CIRCULATIONAHA.105.560177
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2006;113:90-97.)
© 2006 American Heart Association, Inc.
Vascular Medicine |
Pharmacological Activation of Liver X Receptors Promotes Reverse Cholesterol Transport In Vivo
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.
CLINICAL PERSPECTIVE
This article has been cited by other articles:
 |
|
 |
|
  I. T. Cook, Z. Duniec-Dmuchowski, T. A. Kocarek, M. Runge-Morris, and C. N. Falany 24-Hydroxycholesterol Sulfation by Human Cytosolic Sulfotransferases: Formation of Monosulfates and Disulfates, Molecular Modeling, Sulfatase Sensitivity, and Inhibition of Liver X Receptor Activation Drug Metab. Dispos., October 1, 2009; 37(10): 2069 - 2078. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-K. Kim, V. Meliton, K. W. Park, C. Hong, P. Tontonoz, P. Niewiadomski, J. A. Waschek, S. Tetradis, and F. Parhami Negative Regulation of Hedgehog Signaling by Liver X Receptors Mol. Endocrinol., October 1, 2009; 23(10): 1532 - 1543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rashid, M. Marcil, I. Ruel, and J. Genest Identification of a novel human cellular HDL biosynthesis defect Eur. Heart J., September 2, 2009; 30(18): 2204 - 2212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Tanigawa, J. T. Billheimer, J.-i. Tohyama, I. V. Fuki, D. S. Ng, G. H. Rothblat, and D. J. Rader Lecithin: Cholesterol Acyltransferase Expression Has Minimal Effects on Macrophage Reverse Cholesterol Transport In Vivo Circulation, July 14, 2009; 120(2): 160 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Barlic, W. Zhu, and P. M. Murphy Atherogenic Lipids Induce High-Density Lipoprotein Uptake and Cholesterol Efflux in Human Macrophages by Up-Regulating Transmembrane Chemokine CXCL16 without Engaging CXCL16-Dependent Cell Adhesion J. Immunol., June 15, 2009; 182(12): 7928 - 7936. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. H. Kim, J. M. Yoon, A H. Choi, W. S. Kim, G. Y. Lee, and J. B. Kim Liver X Receptor Ligands Suppress Ubiquitination and Degradation of LXR{alpha} by Displacing BARD1/BRCA1 Mol. Endocrinol., April 1, 2009; 23(4): 466 - 474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Rader, E. T. Alexander, G. L. Weibel, J. Billheimer, and G. H. Rothblat The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis J. Lipid Res., April 1, 2009; 50(Supplement): S189 - S194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Junyent, K. L. Tucker, C. E. Smith, A. Garcia-Rios, J. Mattei, C.-Q. Lai, L. D. Parnell, and J. M. Ordovas The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study J. Lipid Res., March 1, 2009; 50(3): 565 - 573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Rippmann, C. Schoelch, T. Nolte, H. Pavliska, A. van Marle, H. van Es, and J. Prestle Improved lipid profile through liver-specific knockdown of liver X receptor {alpha} in KKAy diabetic mice J. Lipid Res., January 1, 2009; 50(1): 22 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Mukherjee, K. T. Locke, B. Miao, D. Meyers, H. Monshizadegan, R. Zhang, D. Search, D. Grimm, M. Flynn, K. M. O'Malley, et al. Novel Peroxisome Proliferator-Activated Receptor {alpha} Agonists Lower Low-Density Lipoprotein and Triglycerides, Raise High-Density Lipoprotein, and Synergistically Increase Cholesterol Excretion with a Liver X Receptor Agonist J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 716 - 726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Teupser, D. Kretzschmar, C. Tennert, R. Burkhardt, W. Wilfert, D. Fengler, R. Naumann, A. E. Sippel, and J. Thiery Effect of Macrophage Overexpression of Murine Liver X Receptor-{alpha} (LXR-{alpha}) on Atherosclerosis in LDL-Receptor Deficient Mice Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 2009 - 2015. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D J Hausenloy and D M Yellon Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels Postgrad. Med. J., November 1, 2008; 84(997): 590 - 598. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Colin, E. Bourguignon, A.-B. Boullay, J.-J. Tousaint, S. Huet, F. Caira, B. Staels, S. Lestavel, J.-M. A. Lobaccaro, and P. Delerive Intestine-Specific Regulation of PPAR{alpha} Gene Transcription by Liver X Receptors Endocrinology, October 1, 2008; 149(10): 5128 - 5135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Calpe-Berdiel, N. Rotllan, C. Fievet, R. Roig, F. Blanco-Vaca, and J. C. Escola-Gil Liver X receptor-mediated activation of reverse cholesterol transport from macrophages to feces in vivo requires ABCG5/G8 J. Lipid Res., September 1, 2008; 49(9): 1904 - 1911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Tancevski, A. Wehinger, E. Demetz, P. Eller, K. Duwensee, J. Huber, K. Hochegger, W. Schgoer, C. Fievet, F. Stellaard, et al. Reduced Plasma High-Density Lipoprotein Cholesterol in Hyperthyroid Mice Coincides with Decreased Hepatic Adenosine 5'-Triphosphate-Binding Cassette Transporter 1 Expression Endocrinology, July 1, 2008; 149(7): 3708 - 3712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. deGoma, R. L. deGoma, and D. J. Rader Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J. Am. Coll. Cardiol., June 10, 2008; 51(23): 2199 - 2211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D J Hausenloy and D M Yellon Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels Heart, June 1, 2008; 94(6): 706 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Imayama, T. Ichiki, D. Patton, K. Inanaga, R. Miyazaki, H. Ohtsubo, Q. Tian, K. Yano, and K. Sunagawa Liver X Receptor Activator Downregulates Angiotensin II Type 1 Receptor Expression Through Dephosphorylation of Sp1 Hypertension, June 1, 2008; 51(6): 1631 - 1636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Zanotti, F. Poti, M. Pedrelli, E. Favari, E. Moleri, G. Franceschini, L. Calabresi, and F. Bernini The LXR agonist T0901317 promotes the reverse cholesterol transport from macrophages by increasing plasma efflux potential J. Lipid Res., May 1, 2008; 49(5): 954 - 960. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Movva and D. J. Rader Laboratory Assessment of HDL Heterogeneity and Function Clin. Chem., May 1, 2008; 54(5): 788 - 800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zhu, Y. Fu, Y. Hou, N. Wang, Y. Guan, C. Tang, J. Y.-J. Shyy, and Y. Zhu Laminar Shear Stress Regulates Liver X Receptor in Vascular Endothelial Cells Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): 527 - 533. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Tchoua, W. D'Souza, N. Mukhamedova, D. Blum, E. Niesor, J. Mizrahi, C. Maugeais, and D. Sviridov The effect of cholesteryl ester transfer protein overexpression and inhibition on reverse cholesterol transport Cardiovasc Res, March 1, 2008; 77(4): 732 - 739. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Out, W. Jessup, W. Le Goff, M. Hoekstra, I. C. Gelissen, Y. Zhao, L. Kritharides, G. Chimini, J. Kuiper, M. J. Chapman, et al. Coexistence of Foam Cells and Hypocholesterolemia in Mice Lacking the ABC Transporters A1 and G1 Circ. Res., January 4, 2008; 102(1): 113 - 120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Buono, Y. Li, S. W. Waldo, and H. S. Kruth Liver X receptors inhibit human monocyte-derived macrophage foam cell formation by inhibiting fluid-phase pinocytosis of LDL J. Lipid Res., November 1, 2007; 48(11): 2411 - 2418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Tanigawa, J. T. Billheimer, J.-i. Tohyama, Y. Zhang, G. Rothblat, and D. J. Rader Expression of Cholesteryl Ester Transfer Protein in Mice Promotes Macrophage Reverse Cholesterol Transport Circulation, September 11, 2007; 116(11): 1267 - 1273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-D. Wang, V. Franklin, and Y. L. Marcel In Vivo Reverse Cholesterol Transport From Macrophages Lacking ABCA1 Expression Is Impaired Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1837 - 1842. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Tamehiro, Y. Shigemoto-Mogami, T. Kakeya, K.-i. Okuhira, K. Suzuki, R. Sato, T. Nagao, and T. Nishimaki-Mogami Sterol Regulatory Element-binding Protein-2- and Liver X Receptor-driven Dual Promoter Regulation of Hepatic ABC Transporter A1 Gene Expression: MECHANISM UNDERLYING THE UNIQUE RESPONSE TO CELLULAR CHOLESTEROL STATUS J. Biol. Chem., July 20, 2007; 282(29): 21090 - 21099. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sanz, P. R. Moreno, and V. Fuster The Year in Atherothrombosis J. Am. Coll. Cardiol., April 24, 2007; 49(16): 1740 - 1749. [Full Text] [PDF]
|
|
|
|
|
|
R. Asleh, R. Miller-Lotan, M. Aviram, T. Hayek, M. Yulish, J. E. Levy, B. Miller, S. Blum, U. Milman, C. Shapira, et al. Haptoglobin Genotype Is a Regulator of Reverse Cholesterol Transport in Diabetes In Vitro and In Vivo Circ. Res., December 8, 2006; 99(12): 1419 - 1425. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Ikonen Mechanisms for cellular cholesterol transport: defects and human disease. Physiol Rev, October 1, 2006; 86(4): 1237 - 1261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Baldan, L. Pei, R. Lee, P. Tarr, R. K. Tangirala, M. M. Weinstein, J. Frank, A. C. Li, P. Tontonoz, and P. A. Edwards Impaired Development of Atherosclerosis in Hyperlipidemic Ldlr-/- and ApoE-/- Mice Transplanted With Abcg1-/- Bone Marrow Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2301 - 2307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cuchel and D. J. Rader Macrophage Reverse Cholesterol Transport: Key to the Regression of Atherosclerosis? Circulation, May 30, 2006; 113(21): 2548 - 2555. [Full Text] [PDF]
|
|
|
|
|
|
D. Duffy and D. J. Rader Emerging Therapies Targeting High-Density Lipoprotein Metabolism and Reverse Cholesterol Transport Circulation, February 28, 2006; 113(8): 1140 - 1150. [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Lee and J. Plutzky Liver X Receptor Activation and High-Density Lipoprotein Biology: A Reversal of Fortune? Circulation, January 3, 2006; 113(1): 5 - 8. [Full Text] [PDF]
|
|