Accumulation of endoplasmic reticulum stress and lipogenesis in the liver through generational effects of high fat diets
Accumulation of endoplasmic reticulum stress and lipogenesis in the liver through generational effects of high fat diets
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高脂肪饮食的代际效应导致肝脏内质网应激和脂肪生成的积累
DOI：
10.1016/j.jhep.2011.10.018
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发表时间：
2012-04-01
影响因子：
25.7
通讯作者：
Zheng, Ling
中科院分区：
文献类型：
--
作者：
Li, Jiong;Huang, Jin;Zheng, Ling
背景和目标：在过去的十年中，儿童非酒精性脂肪性肝病（NAFLD）的急剧上升不能仅仅解释为儿童高脂肪饮食（HFD）摄入量的增加。最近的研究表明，喂食HFD的母亲的后代在断奶HFD时患上的NAFLD比断奶正常食物（NC）时更严重，这表明前馈循环可能会在多代人中加剧这些综合症。在本研究中，上述前馈循环的小鼠采用连续HFD喂养三generations.Methods：C57 BL/6小鼠喂养与HFD或NC连续三代（F0，F1，和F2）。研究了雄性后代的体重、食物摄入量、肝脏组织学;胰岛素、瘦素和甘油三酯水平;脂肪生成和内质网（ER）应激途径相关因子的表达;以及组蛋白甲基化状态。肥胖发生得更早，一代又一代变得更严重（F2 >F1 >F0），并且伴随着在用跨代HFD喂养的雄性小鼠中脂肪变性的组织学评分的逐渐增加。HFD处理的F2小鼠脂肪变性程度最高，与胰岛素和瘦素水平最高相关。后者小鼠的特征在于增强的脂肪生成和ER应激，检测到LXR α、ERO 1-α、组蛋白甲基化和H3 K9组蛋白甲基转移酶的跨代变化趋势。此外，染色质免疫沉淀（CHIP）试验表明，一个显着减少积累的甲基化组蛋白在LXR α和ERO 1-α基因promoters.Conclusions：在HFD喂养stress. Under，F2代的男性后代（来自祖母和母亲肥胖）是非常容易发展肥胖和肝脂肪变性。这可能是表观遗传修饰的跨代积累导致肝脏中脂肪生成和ER应激途径上调的结果。(c)2011年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: The dramatic rise of nonalcoholic fatty liver disease (NAFLD) among children in the past decade cannot be solely explained by the increased high fat diet (HFD) intake in kids. Recent studies suggest that the offspring of HFD-fed mothers develop a worse form of NAFLD when weaned on the HFD than when weaned on the normal chow (NC), indicating that a feed-forward circle may exacerbate the syndromes throughout multiple generations. In the present study, the aforementioned feed-forward circle was investigated in mice by employing continuous HFD feeding for three generations.Methods: C57BL/6 mice were fed with either a HFD or NC for three consecutive generations (F0, F1, and F2). Body weight, food intake, hepatic histology; levels of insulin, leptin, and triglycerides; expression of factors involved in lipogenesis and endoplasmic reticulum (ER) stress pathways; and histone methylation status were investigated in male offspring.Results: Obesity occurred earlier, became more severe through generations (F2 >F1 >F0), and was accompanied by a gradual increase of histological scoring of steatosis in male mice with transgenerational HFD feeding. The highest degree of steatosis occurred in HFD-treated F2 mice and was associated with the highest levels of insulin and leptin. The latter mice were characterized by enhanced lipogenesis and ER stress with a trend of transgenerational changes was detected for LXR alpha, ERO1-alpha, histone methylations, and H3K9 histone methyltransferase. Furthermore, chromatin immunoprecipitation (CHIP) assay demonstrated a significantly reduced accumulation of methylated histones in LXR alpha and ERO1-alpha gene promoters.Conclusions: Under HFD feeding stress, the male offspring of the F2 generation (derived from both grand-maternal and maternal obesity) are extremely susceptible to developing obesity and hepatic steatosis. This is presumably a consequence of transgenerational accumulation of epigenetic modifications leading to up-regulation of lipogenesis and ER stress pathways in the liver. (c) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.