Abstract
Liver X receptor (LXR) activation represents a mechanism to prevent macrophage foam cell formation. Previously, we demonstrated that partial inhibition of oxidosqualene:lanosterol cyclase (OSC) stimulated synthesis of the LXR agonist 24(S),25-epoxycholesterol (24(S),25-epoxy) and enhanced ABCA1-mediated cholesterol efflux. In contrast to a synthetic, nonsteroidal LXR activator, TO-901317, triglyceride accumulation was not observed. In the present study, we determined whether endogenous 24(S),25-epoxy synthesis selectively enhanced expression of macrophage LXR-regulated cholesterol efflux genes but not genes that regulate fatty acid metabolism. THP-1 human macrophages incubated with the OSC inhibitor (OSCi) RO0714565 (15 nM) significantly reduced cholesterol synthesis and maximized synthesis of 24(S),25-epoxy. Endogenous 24(S),25-epoxy increased ABCA1, ABCG1, and APOE mRNA abundance and consequently increased cholesterol efflux to apoAI. In contrast, OSCi had no effect on LXR-regulated genes LPL (lipoprotein lipase) and FAS (fatty acid synthase). TO-901317 (>or=10 nM) significantly enhanced expression of all genes examined. OSCi and TO-901317 increased the mRNA and precursor form of SREBP-1c, a major regulator of fatty acid and triglyceride synthesis. However, conversion of the precursor to the active form (nSREBP-1c) was blocked by OSCi-induced 24(S),25-epoxy but not by TO-901317 (>or=10 nm), which instead markedly increased nSREBP-1c. Disruption of nSREBP-1c formation by 24(S),25-epoxy accounted for diminished FAS and LPL expression. In summary, endogenous synthesis of 24(S),25-epoxy selectively up-regulates expression of macrophage LXR-regulated cholesterol efflux genes without stimulating genes linked to fatty acid and triglyceride synthesis.
Highlights
In vivo experiments using a synthetic, nonsteroidal Liver X receptor (LXR) agonist, TO-901317, established that liver X receptors (LXRs) activation is integral in attenuating atherosclerosis (10, 11)
Selective activation of LXR-regulated genes involved in macrophage cholesterol efflux and separation of the two LXR-regulated metabolic pathways of cholesterol efflux and triglyceride accumulation represents a potential mechanism for the attenuation of macrophage foam cell formation
We demonstrated that inhibition of oxidosqualene:lanosterol cyclase (OSC) by RO0714565 at a dose that maximizes 24(S),25-epoxy synthesis enhanced cholesterol efflux from cultured mouse macrophages, an effect associated with an LXRinduced increase in the expression of ABCA1 and ABCG1
Summary
The major deleterious effect of treatment of mice with synthetic LXR agonists is a massive increase in plasma and liver triglyceride (10, 11, 15, 16). Lipogenesis and triglyceride accumulation is enhanced by highly potent synthetic LXR agonists that up-regulate expression of SREBP-1c and such downstream genes as FAS and LPL, which, in addition to LXREs, contain sterol response elements (SREs) in their promoter regions (7, 8). We demonstrated that inhibition of OSC by RO0714565 at a dose that maximizes 24(S),25-epoxy synthesis enhanced cholesterol efflux from cultured mouse macrophages, an effect associated with an LXRinduced increase in the expression of ABCA1 and ABCG1. We hypothesized that enhanced synthesis of 24(S),25-epoxy within a physiologically relevant range would lead to functionally significant increases in the expression of LXR-regulated genes ABCA1, ABCG1, and APOE and cholesterol efflux, whereas FAS, LPL, and SREBP-1c would be relatively unaffected. Unlike higher concentrations of TO-901317, the OSCi-induced 24(S),25-epoxy or exogenous 24(S),25-epoxy blocked conversion of the inactive pSREBP-1 to its active nuclear form, which probably accounts for the absence of enhanced FAS and LPL gene expression
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