LXRα is Uniquely Required for Maximal Reverse Cholesterol Transport and Atheroprotection in ApoE-deficient Mice

Overview

Journal J Lipid Res

Publisher Elsevier

Specialty Biochemistry

Date 2012 Mar 29

PMID 22454476

Citations 20

Authors

Cynthia Hong

Michele N Bradley

Xin Rong

Xuping Wang

Alan Wagner

Victor Grijalva

Lawrence W Castellani

Jon Salazar

Susan Realegeno

Rima Boyadjian

Alan M Fogelman

Brian J Van Lenten

Srinivasa T Reddy

Aldons J Lusis

Rajendra K Tangirala

Peter Tontonoz

Affiliations

Soon will be listed here.

Abstract

The liver X receptor (LXR) signaling pathway is an important modulator of atherosclerosis, but the relative importance of the two LXRs in atheroprotection is incompletely understood. We show here that LXRα, the dominant LXR isotype expressed in liver, plays a particularly important role in whole-body sterol homeostasis. In the context of the ApoE(-/-) background, deletion of LXRα, but not LXRβ, led to prominent increases in atherosclerosis and peripheral cholesterol accumulation. However, combined loss of LXRα and LXRβ on the ApoE(-/-) background led to an even more severe cholesterol accumulation phenotype compared to LXRα(-/-)ApoE(-/-) mice, indicating that LXRβ does contribute to reverse cholesterol transport (RCT) but that this contribution is quantitatively less important than that of LXRα. Unexpectedly, macrophages did not appear to underlie the differential phenotype of LXRα(-/-)ApoE(-/-) and LXRβ(-/-)ApoE(-/-) mice, as in vitro assays revealed no difference in the efficiency of cholesterol efflux from isolated macrophages. By contrast, in vivo assays of RCT using exogenously labeled macrophages revealed a marked defect in fecal sterol efflux in LXRα(-/-)ApoE(-/-) mice. Mechanistically, this defect was linked to a specific requirement for LXRα(-/-) in the expression of hepatic LXR target genes involved in sterol transport and metabolism. These studies reveal a previously unrecognized requirement for hepatic LXRα for optimal reverse cholesterol transport in mice.

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References

Tontonoz P, Mangelsdorf D . Liver X receptor signaling pathways in cardiovascular disease. Mol Endocrinol. 2003; 17(6):985-93. DOI: 10.1210/me.2003-0061. View

Yu L, Hammer R, von Bergmann K, Lutjohann D, Cohen J, Hobbs H . Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci U S A. 2002; 99(25):16237-42. PMC: 138595. DOI: 10.1073/pnas.252582399. View

Zelcer N, Tontonoz P . Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest. 2006; 116(3):607-14. PMC: 1386115. DOI: 10.1172/JCI27883. View

Yu L, York J, von Bergmann K, Lutjohann D, Cohen J, Hobbs H . Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP-binding cassette transporters G5 and G8. J Biol Chem. 2003; 278(18):15565-70. DOI: 10.1074/jbc.M301311200. View

Repa J, Berge K, Pomajzl C, Richardson J, Hobbs H, Mangelsdorf D . Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J Biol Chem. 2002; 277(21):18793-800. DOI: 10.1074/jbc.M109927200. View

Glass C, Witztum J . Atherosclerosis. the road ahead. Cell. 2001; 104(4):503-16. DOI: 10.1016/s0092-8674(01)00238-0. View

Rader D, Alexander E, Weibel G, Billheimer J, Rothblat G . The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. J Lipid Res. 2008; 50 Suppl:S189-94. PMC: 2674717. DOI: 10.1194/jlr.R800088-JLR200. View

Tangirala R, Bischoff E, Joseph S, Wagner B, Walczak R, Laffitte B . Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proc Natl Acad Sci U S A. 2002; 99(18):11896-901. PMC: 129365. DOI: 10.1073/pnas.182199799. View

Cuchel M, Rader D . Macrophage reverse cholesterol transport: key to the regression of atherosclerosis?. Circulation. 2006; 113(21):2548-55. DOI: 10.1161/CIRCULATIONAHA.104.475715. View

10.

Hong C, Walczak R, Dhamko H, Bradley M, Marathe C, Boyadjian R . Constitutive activation of LXR in macrophages regulates metabolic and inflammatory gene expression: identification of ARL7 as a direct target. J Lipid Res. 2010; 52(3):531-9. PMC: 3035689. DOI: 10.1194/jlr.M010686. View

11.

Joseph S, Bradley M, Castrillo A, Bruhn K, Mak P, Pei L . LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell. 2004; 119(2):299-309. DOI: 10.1016/j.cell.2004.09.032. View

12.

Yu L, von Bergmann K, Lutjohann D, Hobbs H, Cohen J . Selective sterol accumulation in ABCG5/ABCG8-deficient mice. J Lipid Res. 2003; 45(2):301-7. DOI: 10.1194/jlr.M300377-JLR200. View

13.

Lehrke M, Lebherz C, Millington S, Guan H, Millar J, Rader D . Diet-dependent cardiovascular lipid metabolism controlled by hepatic LXRalpha. Cell Metab. 2005; 1(5):297-308. DOI: 10.1016/j.cmet.2005.04.005. View

14.

Yu L, Gupta S, Xu F, Liverman A, Moschetta A, Mangelsdorf D . Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion. J Biol Chem. 2004; 280(10):8742-7. DOI: 10.1074/jbc.M411080200. View

15.

Bischoff E, Daige C, Petrowski M, Dedman H, Pattison J, Juliano J . Non-redundant roles for LXRalpha and LXRbeta in atherosclerosis susceptibility in low density lipoprotein receptor knockout mice. J Lipid Res. 2010; 51(5):900-6. PMC: 2853457. DOI: 10.1194/jlr.M900096. View

16.

Pawar A, Botolin D, Mangelsdorf D, Jump D . The role of liver X receptor-alpha in the fatty acid regulation of hepatic gene expression. J Biol Chem. 2003; 278(42):40736-43. DOI: 10.1074/jbc.M307973200. View

17.

A-Gonzalez N, Bensinger S, Hong C, Beceiro S, Bradley M, Zelcer N . Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity. 2009; 31(2):245-58. PMC: 2791787. DOI: 10.1016/j.immuni.2009.06.018. View

18.

Joseph S, McKilligin E, Pei L, Watson M, Collins A, Laffitte B . Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci U S A. 2002; 99(11):7604-9. PMC: 124297. DOI: 10.1073/pnas.112059299. View

19.

Villanueva C, Waki H, Godio C, Nielsen R, Chou W, Vargas L . TLE3 is a dual-function transcriptional coregulator of adipogenesis. Cell Metab. 2011; 13(4):413-427. PMC: 3089971. DOI: 10.1016/j.cmet.2011.02.014. View

20.

Marathe C, Bradley M, Hong C, Lopez F, de Galarreta C, Tontonoz P . The arginase II gene is an anti-inflammatory target of liver X receptor in macrophages. J Biol Chem. 2006; 281(43):32197-206. DOI: 10.1074/jbc.M605237200. View