Bisphenol F disrupts lipophagy and lysosomal acidification via ATGL-SIRT1-PPARα signaling in NAFLD-like hepatic changes

Bisphenol F (BPF), a widely used substitute for bisphenol A (BPA), has raised growing concerns due to its potential metabolic toxicity. Recent studies suggest that BPF exposure is associated with lipid accumulation and non-alcoholic fatty liver disease (NAFLD‌)-like changes, however, the underlying mechanisms remain poorly understood. This study was performed to investigate the BPF-induced NAFLD-like changes through the lipid degradative pathway, which via an unrecognized defect of lipophagy mediated by Adipose Triglyceride Lipase (ATGL)-Sirtuin 1 (SIRT1)-Peroxisome proliferator-activated receptor α (PPARα) signaling axis. It showed that BPF significantly suppressed ATGL, SIRT1 and PPARα expression, both in vivo and in vitro study, inhibited lysosomal acidification, and disrupted autophagic flux. Reciprocally, overexpression of ATGL and pharmacological activation of PPARα effectively ameliorated the BPF induced lipid accumulation, defects of autophagic flux, and restored acidification of lysosomes via enhanced Vacuolar-type adenosine triphosphatases (V-ATPase, a proton pump) level. Mechanistically, BPF exposure significantly blocked the Transcription Factor EB (TFEB‌‌) nuclear translocation, and thereby impaired the lysosomal generation and acidification. Intriguingly, pharmacological activation of PPARα facilitated TFEB nuclear translocation and counteracted the BPF-induced lipid deposition. These findings reveal key roles of ATGL-SIRT1-PPARα axis in lipophagy in BPF induced NAFLD-like changes, during which TFEB nuclear translocation played the crucial roles, therefore, targeting lipid degradation pathways may offer potential therapeutic strategies for NAFLD prevention and treatment.