PPARα Senses Bisphenol S to Trigger EP300-Mediated Autophagy Blockage and Hepatic Steatosis.

Abstract

The internal exposure dose of bisphenol S (BPS) is increasing since its use as a substitute for BPA. The relationship between BPS and nonalcoholic liver disease (NAFLD) and the underlying mechanism remain unclarified. In this study, we evaluated the correlation of BPS with NAFLD in populations from the Jiangsu Survey and the 2013-2016 National Health Nutrition Examination Survey and unraveled the molecular pathway by which BPS blocked hepatic autophagy, contributing to lipid accumulation. The study found that serum and urine BPS were associated with NAFLD risks in both the Chinese and US populations. For each additional unit of the BPS level, the NAFLD risk increased by 3.163-fold (serum) and 3.979-fold (urine) in the Chinese population. In addition, after BPS exposure at a dose equivalent to human exposure for 20 weeks, mice developed liver lipid accumulation. BPS could trigger PPARα-mediated transcriptional activation of EP300 expression. BPS promoted the translocation of EP300 from the nucleus to the cytoplasm to regulate the acetylation of Raptor and the activation of mTORC1, which in turn induced autophagy blockage and interfered with lipid degradation in hepatocytes. Conversely, knockdown of EP300 reduced Raptor acetylation and ameliorated autophagy blockage. This study demonstrated that EP300 was a key enzyme for the development of BPS-related NAFLD and provided novel evidence that BPS causes NAFLD.

• Authors: Jingjia Liang, Cheng Xu, Jin Xu, Changjie Yang, Weirui Kong, Zhihao Xiao, Xiu Chen, Qian Liu, Zhenkun Weng, Jun Wang, Guibin Jiang, Zhaoyan Jiang, Aihua Gu
• Journal: Environmental science & technology (Environ Sci Technol) Vol. 57 Issue 51 Pg. 21581-21592 (Dec 26 2023) ISSN: 1520-5851 [Electronic] United States
• PMID: 38085933 (Publication Type: Journal Article)

Chemical References

• PPAR alpha
• Lipids
• Benzhydryl Compounds
• EP300 protein, human
• E1A-Associated p300 Protein

Topics

• Humans
• Mice
• Animals
• Non-alcoholic Fatty Liver Disease (chemically induced)
• PPAR alpha (metabolism)
• Liver (metabolism)
• Autophagy
• Lipids
• Benzhydryl Compounds (toxicity)
• E1A-Associated p300 Protein (metabolism)