LXRα is uniquely required for maximal reverse cholesterol transport and atheroprotection in ApoE-deficient mice[S]

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

Journal of Lipid Research (Jun 2012)

LXRα is uniquely required for maximal reverse cholesterol transport and atheroprotection in ApoE-deficient mice[S]

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

Cynthia Hong: Howard Hughes Medical Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, and
Michele N. Bradley: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, and
Xin Rong: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, and
Xuping Wang: Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Alan Wagner: Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Victor Grijalva: Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Lawrence W. Castellani: Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Jon Salazar: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, and
Susan Realegeno: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, and
Rima Boyadjian: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, and
Alan M. Fogelman: Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Brian J. Van Lenten: Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Srinivasa T. Reddy: Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Aldons J. Lusis: Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Rajendra K. Tangirala: Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
Peter Tontonoz: To whom correspondence should be addressed.; Howard Hughes Medical Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, and; To whom correspondence should be addressed.

Journal volume & issue: Vol. 53, no. 6
pp. 1126 – 1133

Abstract

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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.

Published in Journal of Lipid Research

ISSN: 0022-2275 (Print); 1539-7262 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Chemistry: Organic chemistry: Biochemistry
Website: https://www.journals.elsevier.com/journal-of-lipid-research

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