SIRT1 activator E1231 protects from experimental atherosclerosis and lowers plasma cholesterol and triglycerides by enhancing ABCA1 expression. (July 2018)

• Record Type: Journal Article
• Authors: Feng, Tingting; Liu, Peng; Wang, Xiao; Luo, Jinque; Zuo, Xuan; Jiang, Xinhai; Liu, Chang; Li, Yongzhen; Li, Ni; Chen, Minghua; Zhu, Ningyu; Han, Xiaowan; Liu, Chao; Xu, Yanni; Si, Shuyi
• Is Part Of: Atherosclerosis. Volume 274(2018)
• Page Start: 172
• Page End: 181
• Publication Date: 2018-07
• Subjects: SIRT1 -- LXRα -- ABCA1 -- Cholesterol and lipid metabolism; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2018.04.039
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: 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. Methods: 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. Results: E1231, a piperazine 1, 4-diamide compound, was identified as a SIRT1 activator with EC50 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. Conclusions: 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. Highlights: Compound E1231 was first found and confirmed to be a SIRT1 activator. E1231 regulated ABCA1 expression dependent on SIRT1 in macrophages. E1231 increased cholesterol efflux and decreased lipid accumulation in macrophages dependent on SIRT1 and ABCA1. E1231 regulated cholesterol and lipid metabolism in hyperlipidemia golden hamster. E1231 reduced atherosclerotic plaque development in ApoE −/− mice fed on atherogenic diet.