Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE.

Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE. Research Abstract Details 

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Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE. Abstract Text:

Michelle N Bradley,Cynthia Hong,Mingyi Chen,Sean B Joseph,Damien C Wilpitz,Xuping Wang,Aldons J Lusis,Allan Collins,Willa A Hseuh,Jon L Collins,Rajendra K Tangirala,Peter Tontonoz,

Liver X receptors (LXRs) alpha and beta are transcriptional regulators of cholesterol homeostasis and potential targets for the development of antiatherosclerosis drugs. However, the specific roles of individual LXR isotypes in atherosclerosis and the pharmacological effects of synthetic agonists remain unclear. Previous work has shown that mice lacking LXRalpha accumulate cholesterol in the liver but not in peripheral tissues. In striking contrast, we demonstrate here that LXRalpha(-/-)apoE(-/-) mice exhibit extreme cholesterol accumulation in peripheral tissues, a dramatic increase in whole-body cholesterol burden, and accelerated atherosclerosis. The phenotype of these mice suggests that the level of LXR pathway activation in macrophages achieved by LXRbeta and endogenous ligand is unable to maintain homeostasis in the setting of hypercholesterolemia. Surprisingly, however, a highly efficacious synthetic agonist was able to compensate for the loss of LXRalpha. Treatment of LXRalpha(-/-)apoE(-/-) mice with synthetic LXR ligand ameliorates the cholesterol overload phenotype and reduces atherosclerosis. These observations indicate that LXRalpha has an essential role in maintaining peripheral cholesterol homeostasis in the context of hypercholesterolemia and provide in vivo support for drug development strategies targeting LXRbeta.

Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE. Publishing Authors By Initials

MN Bradley,C Hong,M Chen,SB Joseph,DC Wilpitz,X Wang,AJ Lusis,A Collins,WA Hseuh,JL Collins,RK Tangirala,P Tontonoz,

For similar proteins: receptors, cytoplasmic and nuclear research abstracts see: proteins: receptors, cytoplasmic and nuclear research

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Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: The Journal of clinical investigation

VOLUME: 117

Page Numbers: 2337-46

Journal Abbreviation: J. Clin. Invest.

ISSN: 0021-9738

DAY: 3

MONTH: Aug

YEAR: 2007

Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7802877

Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE. Keywords Mesh Terms:

KEYWORDS: Receptors, Cytoplasmic and Nuclear

MESH TERMS: metabolism

Chemical & Substance for Abstract: Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE. Information

Substance Name: Cholesterol

Registry Number: 57-88-5

Grant and Affiliation Information for Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE.

AFFILIATION: Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, UCLA David Geffen School of Medicine, Los Angeles, California 90095-1662, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: HL69766

ACRONYM: HL

MEDLINETA: J Clin Invest

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