NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China; Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China.
Atherosclerosis. 2018 Jul;274:172-181. doi: 10.1016/j.atherosclerosis.2018.04.039. Epub 2018 Apr 30.
Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent protein deacetylase. Recent studies have demonstrated that enhancing SIRT1 expression or activity may modulate cholesterol and lipid metabolism. However, pharmacological and molecular regulators for SIRT1 are scarce. Here, we aimed to find novel small molecule modulators of SIRT1 to regulate cholesterol and lipid metabolism.
A high-throughput screening assay was established to identify SIRT1 activators. Surface plasmon resonance and immunoprecipitation were performed to confirm the interaction of E1231 with SIRT1. Cholesterol assay was performed to demonstrate the in vitro effect of E1231. The in vivo effect of E1231 was evaluated in experimental models.
E1231, a piperazine 1,4-diamide compound, was identified as a SIRT1 activator with EC value of 0.83 μM. E1231 interacted with recombinant human SIRT1 protein and deacetylated liver X receptor-alpha (LXRα). E1231 increased ATP-binding cassette transporter A1 (ABCA1) expression in RAW 264.7 cells dependent on SIRT1 and LXRα. E1231 promoted cholesterol efflux and inhibited lipid accumulation in RAW 264.7 cells via SIRT1 and ABCA1. In the golden hamster hyperlipidemia model, E1231 treatment decreased total cholesterol and triglyceride levels in both serum and the liver, while increased cholesterol content in feces. Moreover, E1231 increased ABCA1 and SIRT1 protein expression in the liver. In ApoE mice, E1231 treatment reduced atherosclerotic plaque development compared with untreated ApoE mice.
We identified a novel SIRT1 activator E1231 and elucidated its beneficial effects on lipid and cholesterol metabolism. Our study suggests that E1231 might be developed as a novel drug for treating atherosclerosis.
沉默信息调节因子 1（SIRT1）是一种烟酰胺腺嘌呤二核苷酸依赖性蛋白去乙酰化酶。最近的研究表明，增强 SIRT1 的表达或活性可能调节胆固醇和脂质代谢。然而，用于 SIRT1 的药理学和分子调节剂却很少。在此，我们旨在寻找新型小分子 SIRT1 调节剂来调节胆固醇和脂质代谢。
建立了一种高通量筛选测定法来鉴定 SIRT1 激活剂。通过表面等离子体共振和免疫沉淀实验来证实 E1231 与 SIRT1 的相互作用。进行胆固醇测定以证明 E1231 的体外作用。在实验模型中评估 E1231 的体内作用。
E1231，一种哌嗪 1,4-二酰胺化合物，被鉴定为 EC 值为 0.83µM 的 SIRT1 激活剂。E1231 与重组人 SIRT1 蛋白相互作用并使肝 X 受体-α（LXRα）去乙酰化。E1231 在 RAW 264.7 细胞中依赖于 SIRT1 和 LXRα 增加了 ATP 结合盒转运蛋白 A1（ABCA1）的表达。E1231 通过 SIRT1 和 ABCA1 促进 RAW 264.7 细胞中的胆固醇流出并抑制脂质积累。在金黄地鼠高脂血症模型中，E1231 治疗降低了血清和肝脏中的总胆固醇和甘油三酯水平，同时增加了粪便中的胆固醇含量。此外，E1231 增加了肝脏中的 ABCA1 和 SIRT1 蛋白表达。在 ApoE 小鼠中，与未治疗的 ApoE 小鼠相比，E1231 治疗减少了动脉粥样硬化斑块的发展。
我们鉴定出一种新型 SIRT1 激活剂 E1231，并阐明了其对脂质和胆固醇代谢的有益作用。我们的研究表明，E1231 可能被开发为治疗动脉粥样硬化的新型药物。
