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

Abstract

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.

• 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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 117 Issue 8 Pg. 2337-46 (Aug 2007) ISSN: 0021-9738 [Print] United States
• PMID: 17657314 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Apolipoproteins E
• DNA-Binding Proteins
• Ligands
• Liver X Receptors
• Nr1h3 protein, mouse
• Orphan Nuclear Receptors
• Receptors, Cytoplasmic and Nuclear
• Cholesterol

Topics

• Animals
• Apolipoproteins E (deficiency, metabolism)
• Atherosclerosis (drug therapy, genetics, metabolism)
• Cholesterol (metabolism)
• DNA-Binding Proteins (agonists, deficiency, metabolism)
• Drug Design
• Homeostasis (genetics)
• Hypercholesterolemia (drug therapy, genetics, metabolism)
• Ligands
• Liver (metabolism)
• Liver X Receptors
• Macrophage Activation (drug effects, genetics)
• Macrophages (metabolism)
• Mice
• Mice, Knockout
• Orphan Nuclear Receptors
• Phenotype
• Receptors, Cytoplasmic and Nuclear (agonists, deficiency, metabolism)