Downregulation of miR-192 causes hepatic steatosis and lipid accumulation by inducing SREBF1: Novel mechanism for bisphenol A-triggered non-alcoholic fatty liver disease
Downregulation of miR-192 causes hepatic steatosis and lipid accumulation by inducing SREBF1: Novel mechanism for bisphenol A-triggered non-alcoholic fatty liver disease
复制标题
miR-192的下调通过诱导SREBF1导致肝脏脂肪变性和脂质积累：双酚A引发的非酒精性脂肪肝的新机制
DOI：
10.1016/j.bbalip.2017.05.001
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发表时间：
2017-09-01
影响因子：
4.8
通讯作者：
Dong, Sijun
中科院分区：
文献类型：
--
作者：
Lin, Yi;Ding, Dongxiao;Dong, Sijun
暴露于双酚A（BPA）与非酒精性脂肪性肝病（NAFLD）的发生有关，但其潜在机制尚不清楚。鉴于microRNA（miRNA）被认为是脂质代谢的关键调节因子和环境因素的潜在介导因子，本研究旨在探索暴露于BPA触发的肝脏异常脂肪变性和脂质蓄积是否可以通过miR-192调节。我们发现，雄性断奶后C57 BL/6小鼠暴露于50 μ g/kg/天的BPA经口灌胃90天，表现出NAFLD样表型。此外，我们在小鼠肝脏和人HepG 2细胞中发现，BPA诱导的肝脏脂肪变性和脂质蓄积与miR-192表达降低、SREBF 1和一系列参与从头脂肪生成的基因上调相关。BPA暴露肝细胞中miR-192的下调可能是由于DROSHA对前miR-192的加工缺陷所致。使用HepG 2细胞，我们进一步证实了miR-192直接作用于SREBF 1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SREBF 1改善BPA诱导的肝脂肪变性最后，我们注意到，在BPA治疗后，脂质积累并不是小鼠发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 SREBF 1轴的改变引起的。
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 50 mu g/kg/day of BPA by oral gavage for 90 days 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-192SREBF1 axis.