Prenatal caffeine exposure increases the susceptibility to non-alcoholic fatty liver disease in female offspring rats via activation of GR-C/EBPα-SIRT1 pathway
Prenatal caffeine exposure increases the susceptibility to non-alcoholic fatty liver disease in female offspring rats via activation of GR-C/EBPα-SIRT1 pathway
复制标题
产前咖啡因暴露通过激活 GR-C/EBP α-SIRT1 通路增加雌性子代大鼠对非酒精性脂肪肝的易感性
DOI：
10.1016/j.tox.2019.02.008
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发表时间：
2019-04-01
期刊：
影响因子：
4.5
通讯作者：
Wang, Hui
中科院分区：
文献类型：
--
作者：
Hu, Shuwei;Xia, Liping;Wang, Hui
本研究旨在评估产前咖啡因暴露（PCE）诱导的雌性成年后代对非酒精性脂肪性肝病（NAFLD）的易感性，并探讨潜在的编程机制。妊娠大鼠在妊娠第9-20天（GD）灌胃给予咖啡因（30、60和120 mg/kg.d）。将雌性成年子代随机分为3组：出生后10-12周（PW）无慢性应激组和PW 28组。结果表明，PW 28 PCE雌性后代具有较高的肝脏甘油三酯含量和Kleiner评分，伴随着血清皮质酮水平升高。此外，肝糖皮质激素受体（GR），CCAAT增强子结合蛋白α（C/EBP α），脂肪酸合成酶（FXR）和转录因子-固醇调节元件结合蛋白1c（SREBP 1c）的表达水平增加，但SIRT 1表达下降。慢性应激的胎鼠和PW 12后代表现出与PW 28后代相似的变化，伴随着SREBP 1c和FREBP 1c基因启动子中H3 K14 ac和H3 K27 ac水平的增加。用皮质醇处理L02细胞也观察到这些作用，并且GR或C/EBP α siRNA或用SIRT 1激动剂白藜芦醇处理部分逆转。综上所述，PCE诱导的高糖皮质激素水平通过激活子宫内GR-C/EBP α-SIRT 1通路增强组蛋白修饰和SREBP 1c和FREBP 1c的表达。这增强了雌性胎儿肝脏甘油三酯的合成，并在整个出生后和成年期持续，增加了对成人NAFLD的易感性。
This study aimed to evaluate female adult offspring induced by prenatal caffeine exposure (PCE) are susceptible to non-alcoholic fatty liver disease (NAFLD) and to explore the underlying programming mechanisms. Pregnant rats were intragastrically administered caffeine (30, 60, and 120 mg/kg.d) on gestational day (GD) 9-20. The female adult offspring were randomly divided into three groups: offspring without or with chronic stress during postnatal week (PW) 10-12 and PW28 offspring. Results showed that PW28 PCE female offspring had a higher hepatic triglyceride content and Kleiner scores, accompanied by elevated serum corticosterone levels. Moreover, the expression levels of hepatic glucocorticoid receptor (GR), CCAAT enhancer binding protein alpha (C/EBP alpha), fatty acid synthetase (FASN) and the transcription factor-sterol regulatory element binding protein 1c (SREBP1c) were increased, but SIRT1 expression was decreased. The fetal rats and PW12 offspring with chronic stress exhibited similar changes as PW28 offspring, accompanied by increased levels of H3K14ac and H3K27ac in the SREBP1c and FASN gene promoters. These effects were also observed by treating L02 cells with cortisol and were partially reversed by GR or C/EBP alpha siRNA or treatment with the SIRT1 agonist resveratrol. Taken together, PCE-induced high glucocorticoids levels enhanced histone modifications and expression of SREBP1c and FASN via activation of the GR-C/EBP alpha-SIRT1 pathway in utero. This enhanced female fetal hepatic triglyceride synthesis and continued throughout postnatal and adult life, increasing the susceptibility to adult NAFLD.