Lin Ren, Wu Dan, Wu Feng-Juan, Meng Yuan, Zhang Jin-Heng, Wang Xiao-Gang, Jia Li-Hong
Department of Child and Adolescent Health, School of Public Health, China Medical University, Shenyang, China.
Front Endocrinol (Lausanne). 2019 Sep 10;10:620. doi: 10.3389/fendo.2019.00620. eCollection 2019.
Accumulating evidence suggests a role of bisphenol A (BPA) in non-alcoholic fatty liver disease (NAFLD), and its mechanism may be related to the up-regulation of lipogenic genes, but the mechanism of BPA induced lipogenic gene expression remains unknown. The aim of this study was to investigate the effects of perinatal exposure to BPA on NAFLD and its mechanisms. Pregnant Sprague-Dawley rats had access to drinking water containing 1 or 10 μg/ml BPA from gestational day 6 to post-natal day 21. For 5 weeks after weaning, offspring drank normal water without BPA. Body weight, lipid profile and the expression of genes or proteins involved in mTOR mediated lipid metabolism and autophagy, as well as inflammatory response were investigated in the 8-wk-old offspring of different genders. The results showed that body weight was increased only in females, however, males, and females from dams treated with BPA had significantly excess visceral adipose tissue, which was consistent with adipocyte hypertrophy. Elevated TG levels and up-regulation of lipogenic genes or proteins in liver, such as sterol regulatory element binding protein 1 (SREBP1), acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FAS) were consistent with increased liver lipid droplets in offspring exposed to BPA. Compared with controls, the protein levels of InsR, p-IRS-1, IRS-1, TSC1, and TSC2 were decreased, p-PI3K, p-Akt (S473), p-Akt (T308), p-mTOR, and mTOR were increased, and the impaired autophagic degradation was evidenced by increased protein levels of p62, although the levels of p-ULK1, Beclin1, and LC3B proteins were increased in liver of BPA-exposed offspring. The levels of TLR4 and NF-κB proteins were also significantly increased, and ERα protein was significantly decreased in BPA-exposed offspring. Our findings indicate that perinatal exposure to BPA causes the development of NAFLD in both female and male offspring, which is associated with up-regulation of lipogenic genes, dysregulated autophagy and activated inflammatory response involving the PI3K/Akt/mTOR and TLR4/NF-κB pathways.
越来越多的证据表明双酚A（BPA）在非酒精性脂肪性肝病（NAFLD）中发挥作用，其机制可能与脂肪生成基因的上调有关，但BPA诱导脂肪生成基因表达的机制仍不清楚。本研究的目的是探讨围产期暴露于BPA对NAFLD的影响及其机制。从妊娠第6天到出生后第21天，怀孕的Sprague-Dawley大鼠饮用含有1或10μg/ml BPA的饮用水。断奶后5周，后代饮用不含BPA的正常水。在8周龄的不同性别的后代中，研究了体重、脂质谱以及参与mTOR介导的脂质代谢和自噬以及炎症反应的基因或蛋白质的表达。结果显示，仅雌性体重增加，然而，来自用BPA处理的母鼠的雄性和雌性后代都有明显过多的内脏脂肪组织，这与脂肪细胞肥大一致。肝脏中甘油三酯水平升高以及脂肪生成基因或蛋白质的上调，如固醇调节元件结合蛋白1（SREBP1）、乙酰辅酶A羧化酶1（ACC1）和脂肪酸合酶（FAS），与暴露于BPA的后代肝脏脂质滴增加一致。与对照组相比，InsR、p-IRS-1、IRS-1、TSC1和TSC2的蛋白质水平降低，p-PI3K、p-Akt（S473）、p-Akt（T308）、p-mTOR和mTOR增加，并且p62蛋白质水平增加证明自噬降解受损，尽管暴露于BPA的后代肝脏中p-ULK1、Beclin1和LC3B蛋白质水平增加。TLR4和NF-κB蛋白质水平也显著增加，并且暴露于BPA的后代中ERα蛋白质显著降低。我们的研究结果表明，围产期暴露于BPA会导致雌性和雄性后代发生NAFLD，这与脂肪生成基因的上调、自噬失调以及涉及PI3K/Akt/mTOR和TLR4/NF-κB途径的炎症反应激活有关。
