Western diet-induced hepatic steatosis and alterations in the liver transcriptome in adult Brown-Norway rats.
Western diet-induced hepatic steatosis and alterations in the liver transcriptome in adult Brown-Norway rats.
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DOI：
10.1186/s12876-015-0382-3
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发表时间：
2015-10-30
影响因子：
2.4
通讯作者：
Rector RS
中科院分区：
文献类型：
--
作者：
Roberts MD;Mobley CB;Toedebush RG;Heese AJ;Zhu C;Krieger AE;Cruthirds CL;Lockwood CM;Hofheins JC;Wiedmeyer CE;Leidy HJ;Booth FW;Rector RS
本研究的目的是研究亚慢性高脂肪、高糖饮食（也称为"西化饮食"或WD）喂养对早期非酒精性脂肪性肝病（NAFLD）发展过程中肝脏转录组的影响。将Brown Norway雄性大鼠（9月龄）随机分配为随意接受对照（CTL; 14%kcal脂肪，1.2%蔗糖重量）饮食或WD（42%kcal脂肪，34%蔗糖重量）饮食6周。喂养WD六周导致肝脂肪变性发展，如肝三酰甘油含量增加2.25倍所证明，但不诱导晚期肝病（即，无明显炎症或纤维化）。RNA深度测序（RNA-seq）揭示了94种转录物在肝脏中被WD喂养改变（46种上调，48种下调，FDR <0.05）。具体而言，WD喂养的最高差异调节基因网络是"脂质代谢、小分子生物化学、维生素和矿物质代谢"（免疫途径分析（IPA）评分61）。WD喂养大鼠中最高调节的经典信号传导途径是"胆固醇生物合成的超级途径"（10/29个基因受到调节，p = 1.68 E-17），这与WD喂养大鼠中血清胆固醇水平升高的趋势一致（p = 0.09）。值得注意的是，肝脏硬脂酰辅酶A去饱和酶（Scd）mRNA表达是迄今为止在WD喂养大鼠中诱导最高的转录物（约30倍，FDR = 0.01），这支持了先前文献强调该基因是NAFLD发展过程中的关键靶标。总之，亚慢性WD喂养似乎在6周内增加了肝脂肪变性的发展，但仅诱导选择的炎症相关肝脏转录本，主要是急性期反应基因。这些发现继续概述了在明显的肝脏炎症和晚期肝病之前NAFLD发展的早期阶段。
The purpose of this study was to investigate the effects of sub-chronic high fat, high sucrose diet (also termed ‘Westernized diet’ or WD) feeding on the liver transcriptome during early nonalcoholic fatty liver disease (NAFLD) development. Brown Norway male rats (9 months of age) were randomly assigned to receive ad libitum access to a control (CTL; 14 % kcal fat, 1.2 % sucrose by weight) diet or WD (42 % kcal from fat, 34 % sucrose by weight) for 6 weeks. Six weeks of WD feeding caused hepatic steatosis development as evidenced by the 2.25-fold increase in liver triacylglycerol content, but did not induce advanced liver disease (i.e., no overt inflammation or fibrosis) in adult Brown Norway rats. RNA deep sequencing (RNA-seq) revealed that 94 transcripts were altered in liver by WD feeding (46 up-, 48 down-regulated, FDR < 0.05). Specifically, the top differentially regulated gene network by WD feeding was ‘Lipid metabolism, small molecular biochemistry, vitamin and mineral metabolism’ (Ingenuity Pathway Analysis (IPA) score 61). The top-regulated canonical signaling pathway in WD-fed rats was the ‘Superpathway of cholesterol biosynthesis’ (10/29 genes regulated, p = 1.68E-17), which coincides with a tendency for serum cholesterol levels to increase in WD-fed rats (p = 0.09). Remarkably, liver stearoyl-CoA desaturase (Scd) mRNA expression was by far the most highly-induced transcript in WD-fed rats (approximately 30-fold, FDR = 0.01) which supports previous literature underscoring this gene as a crucial target during NAFLD development. In summary, sub-chronic WD feeding appears to increase hepatic steatosis development over a 6-week period but only induces select inflammation-related liver transcripts, mostly acute phase response genes. These findings continue to outline the early stages of NAFLD development prior to overt liver inflammation and advanced liver disease.