Berry intake changes hepatic gene expression and DNA methylation patterns associated with high-fat diet
Berry intake changes hepatic gene expression and DNA methylation patterns associated with high-fat diet
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DOI：
10.1016/j.jnutbio.2015.08.022
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发表时间：
2016-01-01
影响因子：
5.6
通讯作者：
Holm, Cecilia
中科院分区：
文献类型：
--
作者：
Heyman-Linden, Lovisa;Seki, Yoshinori;Holm, Cecilia
肝脏是调节能量平衡的重要器官，脂肪肝与肥胖和胰岛素抵抗密切相关。我们之前已经发现，在高脂(HF)喂养的C57BL/6J小鼠模型中，越橘、黑醋栗和越橘可以预防肝脏脂肪变性和肥胖的发展，而刺梨则会加剧肝脏脂肪变性和肥胖。在这项后续研究中，我们调查了这些影响背后的机制。全基因组肝脏基因表达谱显示，越橘和越橘的保护作用是由于急性期和炎症途径(如Saa1、CXCL1、Lcn2)相关基因的数倍下调所致。相比之下，喂饲ACAI的小鼠表现出与脂肪变性相关的基因(如CFD、CIDA、CRAT)以及脂肪和胆固醇生物合成的显著上调，这与这些小鼠因HF导致的肝脏脂肪变性的加重是一致的。在电子转录因子分析和免疫印迹分析中发现，NF-kappa B、STAT3和mTOR是参与调节所观察到的转录效应的上游调控因子。为了进一步了解基因表达变化所涉及的机制，使用帮助标签试验来识别差异甲基化的CpG位点。与HF对照组相比，越橘诱导了全基因组范围的高甲基化和Ncor2的特异性高甲基化，编码了参与代谢稳态和炎症调节的辅阻遏子NCoR/SMRT。我们的结论是，越橘和越橘的有益代谢作用与下调炎症途径有关，而对于发挥相似代谢作用的黑醋栗来说，不同的作用机制似乎起主导作用。核因子-kappa B、STAT3和mTOR是浆果促进健康作用的潜在靶点。(C)2015年提交人。由爱思唯尔公司出版。
The liver is a critical organ for regulation of energy homeostasis and fatty liver disease is closely associated with obesity and insulin resistance. We have previously found that lingonberries, blackcurrants and bilberries prevent, whereas acai berries exacerbate, the development of hepatic steatosis and obesity in the high-fat (HF)-fed C57BL/6J mouse model. In this follow-up study, we investigated the mechanisms behind these effects. Genome-wide hepatic gene expression profiling indicates that the protective effects of lingonberries and bilberries are accounted for by several-fold downregulation of genes involved in acute-phase and inflammatory pathways (e.g. Saa1, Cxcl1, Lcn2). In contrast, acai-fed mice exhibit marked upregulation of genes associated with steatosis (e.g. Cfd, Cidea, Crat) and lipid and cholesterol biosynthesis, which is in line with the exacerbation of HF-induced hepatic steatosis in these mice. In silico transcription factor analysis together with immunoblot analysis identified NF-kappa B, STAT3 and mTOR as upstream regulators involved in mediating the observed transcriptional effects. To gain further insight into mechanisms involved in the gene expression changes, the HELP-tagging assay was used to identify differentially methylated CpG sites. Compared to the HF control group, lingonberries induced genome-wide hypermethylation and specific hypermethylation of Ncor2, encoding the corepressor NCoR/SMRT implicated in the regulation of pathways of metabolic homeostasis and inflammation. We conclude that the beneficial metabolic effects of lingonberries and bilberries are associated with downregulation of inflammatory pathways, whereas for blackcurrants, exerting similar metabolic effects, different mechanisms of action appear to dominate. NF-kappa B, STAT3 and mTOR are potential targets of the health-promoting effects of berries. (C) 2015 The Authors. Published by Elsevier Inc.