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siRNA nanoparticle targeting Usp20 lowers lipid levels and ameliorates metabolic syndrome in mice

Journal of lipid research. 2024-08; 
Yi Ding 1, Qiu-Bing Chen , Hui Xu , Dilare Adi , Yi-Wen Ding , Wen-Jun Luo , Wen-Zhuo Zhu , Jia-Chen Xu , Xiaolu Zhao , Xiong-Jie Shi , Jie Luo , Hao Yin , Xiao-Yi Lu
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摘要

Atherosclerotic cardiovascular disease (ASCVD) is closely correlated with elevated low-density lipoprotein cholesterol (LDL-C). In feeding state, glucose and insulin activate mTORC1 that phosphorylates the deubiquitylase USP20. USP20 then stabilizes HMG-CoA reductase (HMGCR), thereby increasing lipid biosynthesis. In this study, we applied clinically approved lipid nanoparticles (LNPs) to encapsulate the siRNA targeting Usp20. We demonstrated that silencing of hepatic Usp20 by siRNA decreased body weight, improved insulin sensitivity and increased energy expenditure through elevating UCP1. In Ldlr-/- mice, silencing Usp20 by siRNA decreased lipid levels and prevented atherosclerosis. This study suggests that th... More

关键词

Atherosclerosis; Cholesterol; HMGCR; Lipid nanoparticles; USP20.