Roberts Michael D, Mobley C Brooks, Toedebush Ryan G, Heese Alexander J, Zhu Conan, Krieger Anna E, Cruthirds Clayton L, Lockwood Christopher M, Hofheins John C, Wiedmeyer Charles E, Leidy Heather J, Booth Frank W, Rector R Scott
School of Kinesiology, Auburn University, Auburn, AL, USA.
Edward Via College of Osteopathic Medicine-Auburn Campus, Auburn, AL, USA.
BMC Gastroenterol. 2015 Oct 30;15:151. doi: 10.1186/s12876-015-0382-3.
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.
本研究旨在探讨亚慢性高脂高糖饮食（也称为“西式饮食”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9月龄的雄性挪威棕鼠随机分为两组，一组随意进食对照（CTL）饮食（14%千卡脂肪，1.2%重量的蔗糖），另一组进食WD（42%千卡脂肪，34%重量的蔗糖），持续6周。
喂养WD 6周导致肝脏脂肪变性，肝脏三酰甘油含量增加2.25倍即证明了这一点，但在成年挪威棕鼠中未诱发晚期肝病（即无明显炎症或纤维化）。RNA深度测序（RNA-seq）显示，喂养WD后肝脏中有94个转录本发生改变（46个上调，48个下调，FDR<0.05）。具体而言，喂养WD后差异调节最显著的基因网络是“脂质代谢、小分子生物化学、维生素和矿物质代谢”（ Ingenuity通路分析（IPA）得分61）。喂养WD的大鼠中上调最显著的经典信号通路是“胆固醇生物合成的超级通路”（29个基因中有10个被调节，p = 1.68E - 17），这与喂养WD的大鼠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表达是喂养WD的大鼠中诱导程度最高的转录本（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点。
总之，亚慢性WD喂养在6周内似乎会增加肝脏脂肪变性的发展，但仅诱导一些与炎症相关的肝脏转录本，主要是急性期反应基因。这些发现继续勾勒出NAFLD在明显肝脏炎症和晚期肝病之前的早期发展阶段。
