The mechanism of bisphenol a atherogenicity involves apolipoprotein A‐I downregulation through NF‐κB activation

Abstract

Apolipoprotein A‐I (apoA‐I) is the major protein component of high‐density lipoproteins (HDL), mediating many of its atheroprotective properties. Increasing data reveal the pro‐atherogenic effects of bisphenol A (BPA), one of the most prevalent environmental chemicals. In this study, we investigated the mechanisms by which BPA exerts pro‐atherogenic effects. For this, LDLR−/− mice were fed with a high‐fat diet and treated with 50 μg BPA/kg body weight by gavage. After two months of treatment, the area of atherosclerotic lesions in the aorta, triglycerides and total cholesterol levels were significantly increased, while HDL‐cholesterol was decreased in BPA‐treated LDLR−/− mice as compared to control mice. Real‐Time PCR data showed that BPA treatment decreased hepatic apoA‐I expression. BPA downregulated the activity of the apoA‐I promoter in a dose‐dependent manner. This inhibitory effect was mediated by MEKK1/NF‐κB signaling pathways. Transfection experiments using apoA‐I promoter deletion mutants, chromatin immunoprecipitation, and protein‐DNA interaction assays demonstrated that treatment of hepatocytes with BPA induced NF‐κB signaling and thus the recruitment of p65/50 proteins to the multiple NF‐κB binding sites located in the apoA‐I promoter. In conclusion, BPA exerts pro‐atherogenic effects downregulating apoA‐I by MEKK1 signaling and NF‐κB activation in hepatocytes.