Neonatal overfeeding in mice aggravates the development of methionine and choline-deficient diet-induced steatohepatitis in adulthood
Neonatal overfeeding in mice aggravates the development of methionine and choline-deficient diet-induced steatohepatitis in adulthood
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DOI：
10.1016/j.gendis.2017.12.008
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发表时间：
2019-03-01
期刊：
影响因子：
6.8
通讯作者：
Xiao, Xiaoqiu
中科院分区：
文献类型：
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作者：
Du, Juan;Cao, Xuemei;Xiao, Xiaoqiu
早期的过度喂养与成年后的肥胖和胰岛素抵抗有关。在本研究中，我们使用了一种具有良好特征的小鼠模型来研究，在喂养蛋氨酸和胆碱缺乏(MCD)的饮食后，新生儿过度喂养是否增加了非酒精性脂肪性肝炎(NASH)的易感性。每只母猪每窝产仔3只(小窝大小，SL)，而每只母猪10只作为对照(正常窝大小，NL)，以此来诱导新生儿过度喂养。11周龄时，饲喂标准饲料(S)或蛋氨酸胆碱缺乏饲料(MCD)，连续4周。进行糖耐量试验、苏木精-伊红染色、油红O染色和F4/80免疫组织化学、逆转录-定量聚合酶链式反应(RT-qPCR)和Western blotting。与NL小鼠相比，SL小鼠在成年期从2周开始表现出更高的体重增加，成年后表现出更严重的葡萄糖耐受性。3周龄SL小鼠肝脏中固醇调节元件结合蛋白1c和脂肪酸合成酶mRNA的表达水平上调。MCD饮食诱导了典型的NASH，特别是在SL-MCD小鼠，表现为显著的脂肪堆积，大血管脂肪变性，肝细胞肿胀，炎症细胞浸润，肝脏肿瘤坏死因子-α基因表达上调，以及血清丙氨酸转氨酶和天冬氨酸氨基转移酶水平升高。各组大鼠肝纤维化程度无明显差异。MCD饮食对小鼠的代谢功能有不良影响，并可促进NASH的进展，其机制可能与肝细胞脂代谢紊乱和加重肝脏炎症有关。版权所有(C)2018，重庆医科大学。爱思唯尔B.V.制作和主办。
Overfeeding in early life is associated with obesity and insulin resistance in adulthood. In the present study, a well-characterized mouse model was used to investigate whether neonatal overfeeding increases susceptibility to the development of non-alcoholic steatohepatitis (NASH) following feeding with a methionine and choline- deficient (MCD) diet. Neonatal overfeeding was induced by adjusting litters to 3 pups per dam (small litter size, SL) in contrast to 10 pups per dam as control (normal litter size, NL). At 11 weeks of age, mice were fed with standard (S) or a methionine and choline-deficient (MCD) diet for 4 weeks. Glucose tolerance tests, tissue staining with haematoxylin and eosin, oil-red O and immunohistochemistry for F4/80, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were performed. Compared with NL mice, SL mice exhibited higher body weight gain from 2 weeks of age throughout adulthood, and more profound glucose intolerance as adults. Sterol regulatory element-binding protein 1c and fatty acid synthase mRNA expression levels in liver were upregulated in SL mice at 3 weeks of age. MCD diet induced typical NASH, especially in SL-MCD mice, evidenced by marked fat accumulation, macrovescular steatosis, ballooned hepatocytes, inflammatory cells infiltration and tumour necrosis factor-alpha mRNA upregulation in the liver, as well as increased alanine aminotransferase and aspartate aminotransferase levels in the serum. There were no significant differences in liver fibrosis in all groups. Overfeeding during early life exhibited effect with administration of MCD diet in inducing adverse effects on the metabolic function and in promoting the progression of NASH in mice, possibly mediated through dysregulated lipid metabolism in hepatocytes and aggravated hepatic inflammation. Copyright (C) 2018, Chongqing Medical University. Production and hosting by Elsevier B.V.