Key Lab of Urban Environment and Health, Department of Environmental and Molecular Toxicology, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China.
Key Lab of Urban Environment and Health, Department of Environmental and Molecular Toxicology, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China.
Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Sep;1862(9):869-882. doi: 10.1016/j.bbalip.2017.05.001. Epub 2017 May 5.
Exposure to Bisphenol A (BPA) has been associated with the development of nonalcoholic fatty liver disease (NAFLD) but the underlying mechanism remains unclear. Given that microRNA (miRNA) is recognized as a key regulator of lipid metabolism and a potential mediator of environmental cues, this study was designed to explore whether exposure to BPA-triggered abnormal steatosis and lipid accumulation in the liver could be modulated by miR-192. We showed that male post-weaning C57BL/6 mice exposed to 50μg/kg/day of BPA by oral gavage for 90days displayed a NAFLD-like phenotype. In addition, we found in mouse liver and human HepG2 cells that BPA-induced hepatic steatosis and lipid accumulation were associated with decreased expression of miR-192, upregulation of SREBF1 and a series of genes involved in de novo lipogenesis. Downregulation of miR-192 in BPA-exposed hepatocytes could be due to defective pre-miR-192 processing by DROSHA. Using HepG2 cells, we further confirmed that miR-192 directly acted on the 3'UTR of SREBF1, contributing to dysregulation of lipid homeostasis in hepatocytes. MiR-192 mimic and lentivirus-mediated overexpression of miR-192 improved BPA-induced hepatic steatosis by suppressing SREBF1. Lastly, we noted that lipid accumulation was not a strict requirement for developing insulin resistance in mice after BPA treatment. In conclusion, this study demonstrated a novel mechanism in which NAFLD associated with BPA exposure arose from alterations in the miR-192-SREBF1 axis.
双酚 A（BPA）暴露与非酒精性脂肪性肝病（NAFLD）的发展有关，但潜在机制尚不清楚。鉴于 microRNA（miRNA）被认为是脂质代谢的关键调节因子和环境线索的潜在介质，本研究旨在探讨 BPA 引发的异常脂肪变性和肝脏脂质积累是否可以通过 miR-192 来调节。我们表明，通过口服灌胃 90 天每天给予 50μg/kg 的 BPA 暴露的雄性断奶后 C57BL/6 小鼠表现出 NAFLD 样表型。此外，我们在小鼠肝脏和人 HepG2 细胞中发现，BPA 诱导的肝脂肪变性和脂质积累与 miR-192 的表达降低、SREBF1 的上调以及一系列参与从头脂肪生成的基因有关。BPA 暴露的肝细胞中 miR-192 的下调可能是由于 DROSHA 对 pre-miR-192 的加工有缺陷。使用 HepG2 细胞，我们进一步证实 miR-192 直接作用于 SREBF1 的 3'UTR，导致肝细胞中脂质稳态失调。miR-192 模拟物和慢病毒介导的 miR-192 过表达通过抑制 SREBF1 改善 BPA 诱导的肝脂肪变性。最后，我们注意到在 BPA 处理后，脂质积累并不是小鼠产生胰岛素抵抗的严格要求。总之，这项研究证明了一种新的机制，即与 BPA 暴露相关的 NAFLD 是由 miR-192-SREBF1 轴的改变引起的。
