Bisphenol A Promotes Hepatic Lipid Deposition Involving Kupffer Cells

Objective: Bisphenol A(BPA) is one of the most common environmental endocrine disruptors, and promotes hepatic lipid deposition, but the mechanism has not been fully elucidated. The polarization of Kupffer cells(KCs) plays an important role in hepatic inflammation by promoting pro-inflammatory M1 phenotype(M1KCs), which contributes to dysregulated lipid metabolism. The purpose of this study is to investigate the role of KC polarization in BPA-induced hepatosteatosis.Methods: In vivo, CD1 mice were fed with different BPA containing diets(0, 5, 50, 500 μg/kg/day) for 8 weeks, the content of hepatic triglyceride(TG) was tested using enzymic assay kit, oil red O staining was used to determine the intracellular lipid droplet formation. Real-time PCR and protein chip were used to detect the expression of hepatic inflammation factors. The identification of KCs and quantification of M1 KCs were performed by flow cytometer analysis. In vitro, primary KCs were cultured and treated with BPA(10μM), LPS(100ng/ml) and estrogen receptor(ER) antagonist ICI 182789(ICI) respectively, or treated with BPA combined with ICI for 24 h. Different methods were used to detect the above indicators. Hep G2 cells were treated with the supernatant from 0μM, 10μM BPA or 100ng/ml LPS treated KCs, named as Ctrl-KCs, BPA-KCs and LPS-KCs group, different methods were used to determine the hepatic lipid deposition.Results: In vivo, compared with control group, the level of TG was significantly higher in BPA groups, oil red O staining also showed that BPA promoted lipid accumulation. In BPA groups, the expression of SREBP1 and FAS were increased, the expression of PPARα、MTP and ATGL were decreased. The expression of TNFα 、 IL-1β 、 IL-6 and MCP-1 were increased in BPA groups compared with control group. In BPA groups, the quantification of M1 KCs were increased significantly. In vitro, the expression of inflammation factors were higher in BPA group than in control group, as well as the quantification of M1 KCs. TG content quantification test showed that compared with Ctrl-KCs group, intracellular TG contents were increased in BPA-KCs and LPS-KCs groups. Oil Red O staining displayed the contents of intracellular fat were more obvious in BPA-KCs and LPS-KCs groups than Ctrl-KCs group. Compared with BPA-treated cells, the ratio of M1 type of KCs was significantly decreased after the treatment of ICI as assayed by flow cytometry analysis.Conclusion: M1 KCs polarization is involved in BPA-induced hepatic fat deposition, which is possibly associated with the estrogen receptor signaling pathway.