HNF4A as a potential target of PFOA and PFOS leading to hepatic steatosis: Integrated molecular docking, molecular dynamic and transcriptomic analyses

Li, Rui; Zhang, Zijing; Xuan, Yuxin; Wang, Yulu; Zhong, Yuyan; Zhang, Lingyin; Zhang, Jinrui; Chen, Qian; Yu, Shuling; Yuan, Jintao

doi:10.1016/j.cbi.2024.110867

Cited by 5 publications

(2 citation statements)

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“…This difference could be attributed to a longer exposure period of 7 days, in comparison to the 3 days utilized in our study. Increased triglyceride levels as well as altered lipid and cholesterol metabolism genes in mice livers have also been seen in human cells [ 33 , 34 ]. These studies have suggested an involvement of the PPARα receptor [ 33 ], as well as the Hepatocyte Nuclear Factor 4 alpha (HNF4α) transcription factor [ 34 ], in the steatogenic effect of PFOA.…”

Section: Discussionmentioning

confidence: 99%

“…Increased triglyceride levels as well as altered lipid and cholesterol metabolism genes in mice livers have also been seen in human cells [ 33 , 34 ]. These studies have suggested an involvement of the PPARα receptor [ 33 ], as well as the Hepatocyte Nuclear Factor 4 alpha (HNF4α) transcription factor [ 34 ], in the steatogenic effect of PFOA. The PPARα receptor is generally considered to be the primary target of PFOA [ 35 , 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

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Synergistic Steatosis Induction in Mice: Exploring the Interactions and Underlying Mechanisms between PFOA and Tributyltin

Dauwe,

Mary,

Oliviero

et al. 2024

Cells

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This study explores the impact of environmental pollutants on nuclear receptors (CAR, PXR, PPARα, PPARγ, FXR, and LXR) and their heterodimerization partner, the Retinoid X Receptor (RXR). Such interaction may contribute to the onset of non-alcoholic fatty liver disease (NAFLD), which is initially characterized by steatosis and potentially progresses to steatohepatitis and fibrosis. Epidemiological studies have linked NAFLD occurrence to the exposure to environmental contaminants like PFAS. This study aims to assess the simultaneous activation of nuclear receptors via perfluorooctanoic acid (PFOA) and RXR coactivation via Tributyltin (TBT), examining their combined effects on steatogenic mechanisms. Mice were exposed to PFOA (10 mg/kg/day), TBT (5 mg/kg/day) or a combination of them for three days. Mechanisms underlying hepatic steatosis were explored by measuring nuclear receptor target gene and lipid metabolism key gene expressions, by quantifying plasma lipids and hepatic damage markers. This study elucidated the involvement of the Liver X Receptor (LXR) in the combined effect on steatosis and highlighted the permissive nature of the LXR/RXR heterodimer. Antagonistic effects of TBT on the PFOA-induced activation of the Pregnane X Receptor (PXR) and Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) were also observed. Overall, this study revealed complex interactions between PFOA and TBT, shedding light on their combined impact on liver health.

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