1. Academic Validation
  2. Role of Selenoprotein W in participating in the progression of non-alcoholic fatty liver disease

Role of Selenoprotein W in participating in the progression of non-alcoholic fatty liver disease

  • Redox Biol. 2024 Mar 5:71:103114. doi: 10.1016/j.redox.2024.103114.
Zhiruo Miao 1 Wei Wang 2 Zhiying Miao 3 Qiyuan Cao 1 Shiwen Xu 4
Affiliations

Affiliations

  • 1 College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
  • 2 College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, 310000, People's Republic of China.
  • 3 College of Life Science, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
  • 4 College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China. Electronic address: shiwenxu@neau.edu.cn.
Abstract

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease worldwide. Numerous evidence has demonstrated that metabolic reprogramming serves as a hallmark associated with an elevated risk of NAFLD progression. Selenoprotein W (SelW) is an extensively expressed hepatic selenoprotein that plays a crucial role in antioxidant function. Here, we first demonstrated that SelW is a significantly distinct factor in the liver tissue of NAFLD patients through the Gene Expression Omnibus (GEO) database. Additionally, loss of SelW alleviated hepatic steatosis induced by a high-fat diet (HFD), and was accompanied by the regulation of metabolic and inflammatory pathways as verified by transcriptomic analysis. Moreover, co-immunoprecipitation (CO-IP), liquid chromatography-tandem mass spectrometry (LC-MS), laser scanning confocal microscopy (LSCM) and molecular docking analysis were subsequently implemented to identify Pyruvate Kinase M2 (PKM2) as a potential interacting protein of SelW. Meanwhile, SelW modulated PKM2 translocation into the nucleus to trigger transactivation of the HIF-1α, in further mediating mitochondrial Apoptosis, eventually resulting in mitochondrial damage, ROS excessive production and mtDNA leakage. Additionally, mito-ROS accumulation induced the activation of the NLRP3 inflammasome-mediated Pyroptosis, thereby facilitating extracellular leakage of mtDNA. The escaped mtDNA then evokes the cGAS-STING signaling pathway in macrophage, thus inducing a shift in macrophage phenotype. Together, our results suggest SelW promotes hepatocyte Apoptosis and Pyroptosis by regulating metabolic reprogramming to activate cGAS/STING signaling of macrophages, thereby exacerbating the progression of NAFLD.

Keywords

Glycolysis; Metabolism; Non-alcoholic fatty liver disease; Pyroptosis; Pyruvate kinase M2; Selenoprotein W.

Figures
Products