Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Atherosclerosis. 2012 Jun;222(2):382-9. doi: 10.1016/j.atherosclerosis.2012.02.014. Epub 2012 Mar 3.
Pharmacological LXR activation has anti-atherosclerotic actions in animal models. Part of these beneficial effects may be explained by accelerated reverse cholesterol transport since both plasma high density lipoprotein (HDL) cholesterol and fecal neutral sterol secretion are higher upon LXR activation. Mechanisms underlying these LXR-mediated effects have not been fully elucidated.
We investigated the roles of the isoforms LXRα and LXRβ and the HDL cholesterol uptake receptor SR-B1 in modulation of cholesterol metabolism upon treatment of mice with the LXR ligand T0901317.
HDL cholesterol was maximally 60% increased in a time-dependent fashion due to appearance of more and larger HDL particles. Fecal neutral sterol secretion was maximally induced after 1 week treatment. T0901317 treatment induced fecal neutral sterol secretion by ~300% in wild-type but not in Lxrα deficient mice. Surprisingly, LXR activation reduced SR-B1 protein amount in hepatic membranes, suggesting that this might contribute to elevated HDL cholesterol. However, T0901317 still elevated plasma HDL cholesterol in Sr-b1 deficient mice, suggesting that SR-B1 is not the only step involved in LXR-mediated induction of plasma HDL cholesterol. In addition, SR-B1 is not essential for LXR-induced cholesterol removal from the body.
Induction of fecal neutral sterol secretion by T0901317 critically depends on LXRα but not on LXRβ. LXR activation reduces SR-B1 in hepatic membranes, probably partly contributing to elevated HDL cholesterol. SR-B1 is not required to enhance fecal neutral sterol secretion.
在动物模型中，药理学 LXR 激活具有抗动脉粥样硬化作用。这些有益作用的部分原因可能是由于胆固醇逆向转运加速，因为 LXR 激活后血浆高密度脂蛋白（HDL）胆固醇和粪便中性固醇分泌均升高。这些 LXR 介导的作用的机制尚未完全阐明。
我们研究了 LXRα和 LXRβ异构体以及 HDL 胆固醇摄取受体 SR-B1 在 LXR 配体 T0901317 处理小鼠时对胆固醇代谢的调节作用。
HDL 胆固醇呈时间依赖性最大增加 60％，原因是出现更多和更大的 HDL 颗粒。粪便中性固醇分泌在治疗 1 周后最大诱导。T0901317 处理在野生型小鼠中诱导粪便中性固醇分泌增加约 300％，但在 Lxrα缺陷型小鼠中则没有。令人惊讶的是，LXR 激活减少了肝细胞膜中的 SR-B1 蛋白量，表明这可能有助于升高 HDL 胆固醇。然而，T0901317 仍可使 Sr-b1 缺陷型小鼠的血浆 HDL 胆固醇升高，表明 SR-B1 不是 LXR 介导的血浆 HDL 胆固醇诱导的唯一步骤。此外，SR-B1 对于 LXR 诱导的胆固醇从体内清除不是必需的。
T0901317 诱导粪便中性固醇分泌的关键取决于 LXRα而不是 LXRβ。LXR 激活减少肝细胞膜中的 SR-B1，可能部分有助于升高 HDL 胆固醇。SR-B1 不需要增强粪便中性固醇分泌。
