T‐0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor‐deficient mice

FEBS Letters

Hiroshima, Ayano²  Nakai, Daisuke¹  Ubukata, Naoko²  Morikawa, Yuka²  Inaba, Toshimori²  Koieyama, Tadashi²  Terasaka, Naoki² 

[1] Pharmacokinetics and Drug Delivery Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan

关键词: Liver X receptor;    Nuclear receptor;    ATP binding cassette A1;    Cholesterol efflux;    Macrophage;    Atherosclerosis;    LXR;    liver X receptor;    VLDL;    very low density lipoprotein;    LDL;    low density lipoprotein;    HDL;    high density lipoprotein;    ABC;    ATP binding cassette;    apoA-I;    apolipoprotein A-I;    TC;    total cholesterol;    TG;    triglycerides;    HPLC;    high performance liquid chromatography;    SREBP-1c;    sterol response element binding protein 1c;    FAS;    fatty acid synthetase;    SCD-1;    stearoyl CoA desaturase 1;   

DOI  :  10.1016/S0014-5793(02)03578-0

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Liver X receptors (LXRα and LXRβ) 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.

【 授权许可】

Unknown