Bryan Laffitte1, Joyce J. Repa1,2, Sean B. Joseph1, Damien C. Wilpitz1, Heidi R. Kast-Woelbern1, David J. Mangelsdorf3,1, Peter Tontonoz1
1Howard Hughes Medical Institute, Department of
Pathology and Laboratory Medicine, Department of
Biological Chemistry, and Molecular Biology Institute,
University of California, Los Angeles, CA 90095; and
Department of Pharmacology, University of Texas
Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX
75390
2Physiology
3Biochemistry,
Tóm tắt
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.1) 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.
