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

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.1) and multienhancer 2 (ME.2), that direct macrophage- and adipose-specific expression in transgenic mice. We demonstrate here that the nuclear receptors LXRalpha and LXRbeta 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 Lxralpha-/- or Lxrbeta-/- 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.

Selective Up-regulation of LXR-regulated Genes ABCA1, ABCG1, and APOE in Macrophages through Increased Endogenous Synthesis of 24(S),25-Epoxycholesterol

“…The activation of these three genes by SREBPs has not been directly assessed; presumably, they are not responsive to SREBP-1, since SREs have not been identified for ABCA1 or APOE (41,42). SRE-like elements with only slight similarity to functionally active SREs have been identified for ABCG1 (40).…”

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

“…Pharmacological application of vitamins K-2 and K-3 are also linked to oxidative stress (Gilloteaux et al, 2006;Shibayama-Imazu et al, 2006;Shearer and Newman, 2008;Amalia et al, 2010). APOE is believed to play a role in oxysterol-induced efflux as part of a lipoprotein-mediated defense against oxidative stress (Laffitte et al, 2001;Landes et al, 2003;Carter, 2007;Rezen et al, 2010). Thus, efflux can be viewed as a mechanism to relieve the oxidative stress of excess cholesterol and oxysterols (Galea and Brown, 2009).…”

Macrophages, inflammation, and atherosclerosis

“…27 Two distal enhancers that specify apoE gene expression from macrophages contain conserved liver X receptor (LXR) response elements. 28 There may be a noncooperative assignment to macrophage cholesterol homeostasis for both apoE and ABC-A1, as the absence of apoE causes increased levels of ABC-A1 protein, whereas the expression of apoE reduces ABC-A1 levels. 29 ApoE may be the primary driver of cholesterol efflux in macrophages through a pathway independent from ABC-A1.…”