Ligand activation of LXRβ reverses atherosclerosis and cellular cholesterol overload in mice lacking LXRα and apoE
Michelle N. Bradley, … , Rajendra K. Tangirala, Peter Tontonoz
Michelle N. Bradley, … , Rajendra K. Tangirala, Peter Tontonoz
Published August 1, 2007
Citation Information: J Clin Invest. 2007;117(8):2337-2346. https://doi.org/10.1172/JCI31909.
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Research Article Cardiology

Ligand activation of LXRβ reverses atherosclerosis and cellular cholesterol overload in mice lacking LXRα and apoE

Abstract

Liver X receptors (LXRs) α and β 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 LXRα accumulate cholesterol in the liver but not in peripheral tissues. In striking contrast, we demonstrate here that LXRα–/–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 LXRβ 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 LXRα. Treatment of LXRα–/–apoE–/– mice with synthetic LXR ligand ameliorates the cholesterol overload phenotype and reduces atherosclerosis. These observations indicate that LXRα has an essential role in maintaining peripheral cholesterol homeostasis in the context of hypercholesterolemia and provide in vivo support for drug development strategies targeting LXRβ.

Authors

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

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Figure 6

Treatment of apoE–/– and LXRα–/–apoE–/– mice with synthetic LXR ligand ameliorates the cholesterol overload phenotype.

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Treatment of apoE–/– and LXRα–/–apoE–/– mice with synthetic LXR ligand r...
(A) Whole-body cholesterol levels of apoE–/– or LXRα–/–apoE–/– mice at 25 weeks of age that have been fed a Western diet with or without GW3965 for 22 weeks. n = 3–5 per group. P values are indicated. (B) apoAI- and HDL-specific cholesterol efflux from peritoneal macrophages isolated from apoE–/– or LXRα–/–apoE–/– mice and treated with DMSO or GW3965. Experiments were conducted in quadruplicate. Data are expressed as mean ± SEM. ***P < 0.0005. (C) Basal gene expression in peritoneal macrophages isolated from mice fed a Western diet for 10 days. Data are expressed as mean ± SEM. n = 3 per group. *P < 0.05. (D) Total liver cholesterol levels of apoE–/– or LXRα–/–apoE–/– mice fed a Western diet with or without GW3965. Data are expressed as mean ± SEM. n = 5–8 per group. *P < 0.05.