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. Int. J. Mol. Sci. 2019, 20, 6281 2 of 15 and in apoA-I −/− /LDLR −/− mice [6]. On the other hand, overexpression of human apoA-I reduced atherogenesis in apoE −/− or in LDLR −/− mice [7][8][9][10][11][12][13][14], providing strong evidence for the antiatherogenic role of apoA-I. Recently, it was proposed that the ratio of HDL-cholesterol to apoA-I gives additional insights as a risk marker for cardiovascular disease [15]. To exploit the anti-atherogenic properties of HDL-apoA-I, different approaches, such as pharmacological interventions using HDL-apoA-I mimetic peptides or infusions of apoA-I-containing particles were proposed for the reduction of atherogenesis [16,17].In humans, the APOAI gene is 1.8 Kb in length and it is located on chromosome 11 in the APOAI/APOCIII/APOAIV gene cluster [18]. ApoA-I is synthesized mainly by the liver and the small intestine. APOAI gene expression is mainly regulated at transcriptional level [19]. The APOAI gene promoter contains a TATA box and several cis elements that regulate its gene expression in either a positive or negative manner. Acidosis caused apoA-I downregulation by promoting binding of repressor proteins to a pH-responsive element that overlaps the TATA box within the apoA-I promoter [20]. Several hormones, such as glucocorticoids, thyroid hormones, and insulin, induced APOAI gene expression through a direct mechanism interacting with their specific hormone response elements [21,22]. In humans, treatment with fibrates that interact with a PPAR-responsive element located in the apoA-I promoter increased APOAI gene expression, but opposite effects of fibrates on apoA-I expression were found in r...

Short-Chain Fatty Acids (Except Hexanoic Acid) Lower NF-kB Transactivation, Which Rescues Inflammation-Induced Decreased Apolipoprotein A-I Transcription in HepG2 Cells

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Bisphenol A-induced DNA damages promote to lymphoma progression in human lymphoblastoid cells through aberrant CTNNB1 signaling pathway

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Particulate Matter, an Intrauterine Toxin Affecting Foetal Development and Beyond

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