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  3. Mystery of bisphenol F-induced nonalcoholic fatty liver disease-like changes: Roles of Drp1-mediated abnormal mitochondrial fission in lipid droplet deposition

Mystery of bisphenol F-induced nonalcoholic fatty liver disease-like changes: Roles of Drp1-mediated abnormal mitochondrial fission in lipid droplet deposition

  • Sci Total Environ. 2023 Sep 6;904:166831. doi: 10.1016/j.scitotenv.2023.166831.
Linwei Zhang 1,  Xuexue Xie 1,  Jingxian Tao 2,  Sizhe Wang 1,  Miaoyang Hu 1,  Xi Wang 2,  Zheng Yu 2,  Liuting Xu 2,  Yuxin Lin 2,  Weilan Wu 2,  Jie Cheng 1,  Linlin Wu 3,  Wenwei Liu 4,  Rong Gao 5,  Jun Wang 6
Affiliations

Affiliations

  • 1 Department of Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China.
  • 2 Department of Hygienic Analysis and Detection, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
  • 3 Department of Hygienic Analysis and Detection, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China; The Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi 214000, China.
  • 4 The Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi 214000, China.
  • 5 Department of Hygienic Analysis and Detection, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: gaorong@njmu.edu.cn.
  • 6 Department of Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China; China International Cooperation Center for Environment and Human Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China. Electronic address: wangjun@njmu.edu.cn.
PMID: 37683851 DOI: 10.1016/j.scitotenv.2023.166831
Abstract

As one of the major substitutes for bisphenol A (BPA), bisphenol F (BPF) has been widely used. Our previous study demonstrated that BPF exposure facilitates lipid droplet deposition in hepatic cells, contributing to nonalcoholic fatty liver disease (NAFLD)-like changes. However, the underlying mechanisms remain poorly understood. Here, with a metabolic cage system, we observed the perturbation of energy metabolism in mice treated with BPF. BPF obviously suppressed metabolic capacity, which manifested as decreased energy expenditure, low O2 consumption and CO2 levels in mice. Consistent with the in vivo results, a Seahorse XF Cell Mito Stress Test showed significant reductions in mitochondrial ATP production capacity, maximum respiratory capacity, and residual respiratory capacity after BPF treatment in an in vitro study. Electron microscopy revealed a striking increase in mitochondrial fission that was synchronous with excessive expression and activation of dynamin-related protein 1 (Drp1). Intriguingly, chemical inhibition of Drp1 by Mdivi-1 and/or silencing of Drp1 dramatically hampered mitochondrial fission and ameliorated BPF-induced lipid droplet deposition both in mouse liver and human hepatic cells. Mechanistically, mitochondrial dynamics imbalance played prominent roles in these processes, since suppression of Drp1 by chemical inhibition or knockdown substantially reversed BPF-induced mitochondrial fission and ameliorated the suppression of Mitochondrial Metabolism as well as excessive mitochondrial ROS, which was verified to be key to lipid droplet deposition. Collectively, the findings of the current study reveal previously unrecognized effects involving Drp1-mediated mitochondrial injury in BPF-induced lipid droplet deposition. Therefore, targeted intervention against mitochondrial dysfunction may be a promising therapeutic strategy for BPF-induced NAFLD-like changes.

Keywords

Bisphenol F; Drp1; Mitochondrial fission; Nonalcoholic fatty liver disease.

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