T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice
T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice
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DOI：
10.1016/s0014-5793(02)03578-0
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发表时间：
2003-02-11
期刊：
影响因子：
3.5
通讯作者：
Inaba, T
中科院分区：
文献类型：
--
作者：
Terasaka, N;Hiroshima, A;Inaba, T
肝脏X受体（LXRα和LXRβ）是核受体，是胆固醇和脂质代谢的重要调节因子。 LXR 控制参与巨噬细胞胆固醇流出、肝脏胆汁酸合成和肠道胆固醇吸收的基因。 LXR 还调节参与脂肪生成的基因。为了确定 LXR 的激活是否促进或抑制动脉粥样硬化的发展，将合成 LXR 配体 T-0901317 给予低密度脂蛋白受体 (LDLR)(-/-) 小鼠。 T-0901317 显着减少 LDLR-/- 小鼠的动脉粥样硬化病变，而不影响血浆总胆固醇水平。这种抗动脉粥样硬化作用与 T-0901317 的血浆浓度相关，但与 T-0901317 增加的高密度脂蛋白胆固醇无关。此外，我们观察到 T-0901317 增加了 LDLR-/- 小鼠以及小鼠腹膜巨噬细胞病变中 ATP 结合盒 A1 的表达。 T-0901317 还显着诱导腹膜巨噬细胞中的胆固醇流出活性。这些结果表明LXR配体可能是治疗动脉粥样硬化的有用治疗剂。 (C) 2002 年欧洲生化学会联合会。由 Elsevier Science B.V. 出版。保留所有权利。
Liver X receptors (LXRalpha and LXRbeta) are nuclear receptors, which are important regulators of cholesterol and lipid metabolism. LXRs control genes involved in cholesterol efflux in macrophages, bile acid synthesis in liver and intestinal cholesterol absorption. LXRs also regulate genes participating in lipogenesis. To determine whether the activation of LXR promotes or inhibits development of atherosclerosis, T-0901317, a synthetic LXR ligand, was administered to low density lipoprotein receptor (LDLR)(-/-) mice. T-0901317 significantly reduced the atherosclerotic lesions in LDLR-/- mice without affecting plasma total cholesterol levels. This anti-atherogenic effect correlated with the plasma concentration of T-0901317, but not with high density lipoprotein cholesterol, which was increased by T-0901317. In addition, we observed that T-0901317 increased expression of ATP binding cassette A1 in the lesions in LDLR-/- mice as well as in mouse peritoneal macrophages. T-0901317 also significantly induced cholesterol efflux activity in peritoneal macrophages. These results suggest that LXR ligands may be useful therapeutic agents for the treatment of atherosclerosis. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.