Beyea Michael M, Heslop Claire L, Sawyez Cynthia G, Edwards Jane Y, Markle Janet G, Hegele Robert A, Huff Murray W
Robarts Research Institute Vascular Biology Group, Department of Biochemistry, University of Western, London, Ontario, Canada.
J Biol Chem. 2007 Feb 23;282(8):5207-16. doi: 10.1074/jbc.M611063200. Epub 2006 Dec 23.
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.
肝X受体（LXR）激活是一种防止巨噬细胞泡沫细胞形成的机制。此前，我们证明，氧化鲨烯：羊毛甾醇环化酶（OSC）的部分抑制可刺激LXR激动剂24（S），25 - 环氧胆固醇（24（S），25 - 环氧）的合成，并增强ABCA1介导的胆固醇外流。与合成的非甾体LXR激活剂TO - 901317不同，未观察到甘油三酯积累。在本研究中，我们确定内源性24（S），25 - 环氧的合成是否选择性增强巨噬细胞LXR调节的胆固醇外流基因的表达，而不增强调节脂肪酸代谢的基因的表达。用OSC抑制剂（OSCi）RO0714565（15 nM）孵育THP - 1人巨噬细胞可显著降低胆固醇合成，并使24（S），25 - 环氧的合成最大化。内源性24（S），25 - 环氧增加ABCA1、ABCG1和APOE的mRNA丰度，从而增加胆固醇向载脂蛋白AI的外流。相比之下，OSCi对LXR调节的基因脂蛋白脂肪酶（LPL）和脂肪酸合酶（FAS）没有影响。TO - 901317（≥10 nM）显著增强了所有检测基因的表达。OSCi和TO - 901317增加了脂肪酸和甘油三酯合成的主要调节因子SREBP - 1c的mRNA和前体形式。然而，前体向活性形式（nSREBP - 1c）的转化被OSCi诱导的24（S），25 - 环氧阻断，但未被TO - 901317（≥10 nM）阻断，后者反而显著增加了nSREBP - 1c。24（S），25 - 环氧对nSREBP - 1c形成的破坏导致FAS和LPL表达减少。总之，内源性24（S），25 - 环氧的合成选择性地上调巨噬细胞LXR调节的胆固醇外流基因的表达，而不刺激与脂肪酸和甘油三酯合成相关的基因。
