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Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):781-6. doi: 10.1161/ATVBAHA.109.195693. Epub 2010 Jan 28.

Tissue-specific liver X receptor activation promotes macrophage reverse cholesterol transport in vivo.

Author information

1
Translational Medicine and Therapeutics and Cardiovascular Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA.

Abstract

OBJECTIVE:

We previously reported that a systemic liver X receptor (LXR) agonist promoted macrophage reverse-cholesterol transport (mRCT) in vivo. Because LXR are expressed in multiple tissues involved in RCT (macrophages, liver, intestine), we analyzed the effect of tissue-specific LXR agonism on mRCT.

METHODS AND RESULTS:

In initial studies, the systemic LXR agonist GW3965 failed to promote mRCT in a setting in which LXR was expressed in macrophages but not in liver or intestine. To evaluate the effect of LXR activation specifically in small intestine on mRCT, wild-type mice were treated with either intestinal-specific LXR agonist (GW6340) or systemic LXR agonist (GW3965). Both GW3965 and GW6340 significantly promoted excretion of [(3)H]-sterol in feces by 162% and 52%, respectively. To evaluate the requirement for macrophage LXR activation, we assessed the ability of GW3965 to promote mRCT in wild-type mice using primary macrophages deficient in LXR alpha/beta vs wild-type macrophages. Whereas GW3965 treatment promoted fecal excretion compared with vehicle, its overall ability to promote mRCT was significantly attenuated using LXR alpha/beta knockout macrophages.

CONCLUSIONS:

We demonstrate that intestinal-specific LXR agonism promotes macrophage RCT in vivo and that macrophage LXR itself plays an important, but not predominant, role in promoting RCT in response to an LXR agonist.

PMID:
20110577
PMCID:
PMC3137455
DOI:
10.1161/ATVBAHA.109.195693
[Indexed for MEDLINE]
Free PMC Article

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