2. Academic Validation
  3. siRNA nanoparticle targeting Usp20 lowers lipid levels and ameliorates metabolic syndrome in mice

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

  • J Lipid Res. 2024 Sep;65(9):100626. doi: 10.1016/j.jlr.2024.100626.
Yi Ding 1,  Qiu-Bing Chen 2,  Hui Xu 1,  Dilare Adi 3,  Yi-Wen Ding 1,  Wen-Jun Luo 1,  Wen-Zhuo Zhu 1,  Jia-Chen Xu 1,  Xiaolu Zhao 1,  Xiong-Jie Shi 1,  Jie Luo 1,  Hao Yin 4,  Xiao-Yi Lu 5
Affiliations

Affiliations

  • 1 College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China.
  • 2 Department of Urology, Frontier Science Center for Immunology and Metabolism Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • 3 Heart Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
  • 4 College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China; Department of Urology, Frontier Science Center for Immunology and Metabolism Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • 5 College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China. Electronic address: luxiaoyi@whu.edu.cn.
PMID: 39173829 DOI: 10.1016/j.jlr.2024.100626
Abstract

Atherosclerotic Cardiovascular Disease is closely correlated with elevated low density lipoprotein-cholesterol. In feeding state, glucose and Insulin activate mammalian target of rapamycin 1 that phosphorylates the deubiquitylase ubiquitin-specific peptidase 20 (USP20). USP20 then stabilizes HMG-CoA reductase, thereby increasing lipid biosynthesis. In this study, we applied clinically approved lipid nanoparticles 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 the RNAi-based therapy targeting hepatic Usp20 has a translational potential to treat Metabolic Disease.

Keywords

HMGCR; USP20; atherosclerosis; cholesterol; lipid nanoparticles.

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