School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle Road at University City, Guangzhou, 510006, China.
School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, 100083, China.
Eur J Med Chem. 2019 Nov 15;182:111647. doi: 10.1016/j.ejmech.2019.111647. Epub 2019 Aug 30.
Liver X Receptor (LXR) is a potential drug target for atherosclerosis. One of the major challenges in taking LXR modulators to the clinic is steatosis. It was reported that sterol LXR agonists selectively activate LXR in the intestine and macrophage cells rather than in the liver. We hypothesize that sterol LXR agonists may selectively inhibit atherosclerosis without causing hepatic lipogenesis. Thus, based on LXR structure, 12 sterol compounds were designed and tested in a dual-luciferase reporter gene experiment. It was confirmed that compounds 4 and 6 were LXR agonists. Further experiments demonstrated that compounds 4 and 6 inhibit the formation of macrophage foam cells without inducing triglyceride accumulation in either hepatocytes or adipocytes. In vivo studies demonstrated that compound 4 promotes reverse cholesterol transport without inducing hepatic lipogenesis. Thus, we report that these compounds with sterol scaffolds can be promising leads for the treatment of atherosclerosis without inducing steatosis.
肝 X 受体 (LXR) 是动脉粥样硬化的潜在药物靶点。将 LXR 调节剂应用于临床的主要挑战之一是脂肪变性。有报道称，固醇 LXR 激动剂选择性地在肠道和巨噬细胞中激活 LXR，而不是在肝脏中。我们假设固醇 LXR 激动剂可能选择性地抑制动脉粥样硬化而不引起肝内脂肪生成。因此，基于 LXR 结构，设计并在双荧光素酶报告基因实验中测试了 12 种固醇化合物。证实化合物 4 和 6 是 LXR 激动剂。进一步的实验表明，化合物 4 和 6 抑制巨噬细胞泡沫细胞的形成，而不诱导肝细胞或脂肪细胞中甘油三酯的积累。体内研究表明，化合物 4 促进胆固醇逆转运而不诱导肝内脂肪生成。因此，我们报告说，这些具有固醇支架的化合物可能是治疗动脉粥样硬化而不引起脂肪变性的有希望的先导化合物。
