LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes

Bryan A. Laffitte, Joyce J. Repa, Sean B. Joseph, Damien C. Wilpitz, Heidi R. Kast, David J. Mangelsdorf, Peter Tontonoz

Research output: Contribution to journalArticle

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Abstract

Apolipoprotein E (apoE) secreted by macrophages in the artery wall exerts an important protective effect against the development of atherosclerosis, presumably through its ability to promote lipid efflux. Previous studies have shown that increases in cellular free cholesterol levels stimulate apoE transcription in macrophages and adipocytes; however, the molecular basis for this regulation is unknown. Recently, Taylor and colleagues [Shih, S. J., Allan, C., Grehan, S., Tse, E., Moran, C. & Taylor, J. M. (2000) J. Biol. Chem. 275, 31567-31572] identified two enhancers from the human apoE gene, termed multienhancer 1 (ME.l) and multienhancer 2 (ME.2), that direct macrophage- and adipose-specific expression in transgenic mice. We demonstrate here that the nuclear receptors LXRα and LXRβ and their oxysterol ligands are key regulators of apoE expression in both macrophages and adipose tissue. We show that LXR/RXR heterodimers regulate apoE transcription directly, through interaction with a conserved LXR response element present in both ME.1 and ME.2. Moreover, we demonstrate that the ability of oxysterols and synthetic ligands to regulate apoE expression in adipose tissue and peritoneal macrophages is reduced in Lxrα-/- or Lxrβ-/- mice and abolished in double knockouts. Basal expression of apoE is not compromised in Lxr null mice, however, indicating that LXRs mediate lipid-inducible rather than tissue-specific expression of this gene. Together with our previous work, these findings support a central role for LXR signaling pathways in the control of macrophage cholesterol efflux through the coordinate regulation of apoE, ABCA1, and ABCG1 expression.

Original languageEnglish (US)
Pages (from-to)507-512
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number2
DOIs
StatePublished - Jan 16 2001

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Apolipoproteins E
Adipocytes
Macrophages
Lipids
Genes
Adipose Tissue
Cholesterol
Ligands
Peritoneal Macrophages
Response Elements
Cytoplasmic and Nuclear Receptors
Transgenic Mice
Atherosclerosis
Arteries
Gene Expression

ASJC Scopus subject areas

  • Genetics
  • General

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LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. / Laffitte, Bryan A.; Repa, Joyce J.; Joseph, Sean B.; Wilpitz, Damien C.; Kast, Heidi R.; Mangelsdorf, David J.; Tontonoz, Peter.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 2, 16.01.2001, p. 507-512.

Research output: Contribution to journalArticle

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