Ligand activation of LXRβ reverses atherosclerosis and cellular cholesterol overload in mice lacking LXRα and apoE
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
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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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 2

Quantification of cholesterol levels in tissue, whole mouse, and plasma.

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Quantification of cholesterol levels in tissue, whole mouse, and plasma....
(A) Total liver and skin cholesterol levels of apoE–/– and LXRα–/–apoE–/– mice at 34 weeks of age. Data are expressed as mean ± SEM. n = 5 per group. P value is indicated. (B) Whole-body cholesterol levels of apoE–/– or LXRα–/–apoE–/– mice at 25 weeks of age. n = 4 per group. P value is indicated. (C) Total plasma cholesterol levels of apoE–/– or LXRα–/–apoE–/– mice at 14 and 34 weeks of age. Data are expressed as mean ± SEM. n = 9–15 per group. (D) Fast protein liquid chromatography (FPLC) analysis of plasma cholesterol content of apoE–/– or LXRα–/–apoE–/– mice at 14 weeks of age. Fasting plasma samples from 5 mice of each genotype were pooled for this analysis. (E) Expression of LXR target genes in peritoneal macrophages isolated from apoE–/– or LXRα–/–apoE–/– mice. DMSO (D), 22(R)-, 20α-, and 27-hydroxycholesterol were used at 3 μM, and GW3965 (GW) was used at 1 μM. PLTP, phospholipid transfer protein.