Amelioration of ethanol-induced oxidative stress and alcoholic liver disease by in vivo RNAi targeting Cyp2e1

Yalan Wang; Qiubing Chen; Shuang Wu; Xinyu Sun; Runting Yin; Zhen Ouyang; Hao Yin; Yuan Wei

doi:10.1016/j.apsb.2023.01.009

Amelioration of ethanol-induced oxidative stress and alcoholic liver disease by in vivo RNAi targeting Cyp2e1

Acta Pharm Sin B. 2023 Sep;13(9):3906-3918. doi: 10.1016/j.apsb.2023.01.009. Epub 2023 Feb 24.

Authors

Yalan Wang¹, Qiubing Chen^{2

3}, Shuang Wu¹, Xinyu Sun¹, Runting Yin¹, Zhen Ouyang¹, Hao Yin^{2

3

4

5

6}, Yuan Wei¹

Affiliations

¹ School of Pharmacy, Jiangsu University, Zhenjiang 212013, China.
² Department of Urology, Frontier Science Centre for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
³ Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
⁴ Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
⁵ RNA Institute, Wuhan University, Wuhan 430072, China.
⁶ Wuhan Research Centre for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan 430010, China.

Abstract

Alcoholic liver disease (ALD) results from continuous and heavy alcohol consumption. The current treatment strategy for ALD is based on alcohol withdrawal coupled with antioxidant drug intervention, which is a long process with poor efficacy and low patient compliance. Alcohol-induced CYP2E1 upregulation has been demonstrated as a key regulator of ALD, but CYP2E1 knockdown in humans was impractical, and pharmacological inhibition of CYP2E1 by a clinically relevant approach for treating ALD was not shown. In this study, we developed a RNAi therapeutics delivered by lipid nanoparticle, and treated mice fed on Lieber-DeCarli ethanol liquid diet weekly for up to 12 weeks. This RNAi-based inhibition of Cyp2e1 expression reduced reactive oxygen species and oxidative stress in mouse livers, and contributed to improved ALD symptoms in mice. The liver fat accumulation, hepatocyte inflammation, and fibrosis were reduced in ALD models. Therefore, this study suggested the feasibility of RNAi targeting to CYP2E1 as a potential therapeutic tool to the development of ALD.

Keywords: Alcoholic liver disease; Cyp2e1; Lipid nanoparticle; Lipogenesis; Lipometabolism; Oxidative stress; RNAi; Reactive oxygen species.