Table_2_An integrative approach to assessing effects of a short-term Western diet on gene expression in rat liver.pdf

Consumption of a diet rich in saturated fatty acids and carbohydrates contributes to the accumulation of fat in the liver and development of non-alcoholic steatohepatitis (NASH). Herein we investigated the hypothesis that short-term consumption of a high fat/sucrose Western diet (WD) alters the genomic and translatomic profile of the liver in association with changes in signaling through the protein kinase mTORC1, and that such alterations contribute to development of NAFLD. The results identify a plethora of mRNAs that exhibit altered expression and/or translation in the liver of rats consuming a WD compared to a CD. In particular, consumption of a WD altered the abundance and ribosome association of mRNAs involved in lipid and fatty acid metabolism, as well as those involved in glucose metabolism and insulin signaling. Hepatic mTORC1 signaling was enhanced when rats were fasted overnight and then refed in the morning; however, this effect was blunted in rats fed a WD as compared to a CD. Despite similar plasma insulin concentrations, fatty acid content was elevated in the liver of rats fed a WD as compared to a CD. We found that feeding had a significant positive effect on ribosome occupancy of 49 mRNAs associated with hepatic steatosis (e.g., LIPE, LPL), but this effect was blunted in the liver of rats fed a WD. In many cases, changes in ribosome association were independent of alterations in mRNA abundance, suggesting a critical role for diet-induced changes in mRNA translation in the expression of proteins encoded by those mRNAs. Overall, the findings demonstrate that short-term consumption of a WD impacts hepatic gene expression by altering the abundance of many mRNAs, but also causes wide-spread variation in mRNA translation that potentially contribute to development of hepatic steatosis.

长期摄入富含饱和脂肪酸与碳水化合物的膳食，会促进肝脏脂肪蓄积并诱发非酒精性脂肪性肝炎（non-alcoholic steatohepatitis, NASH）。本研究旨在验证如下假说：短期饲喂高脂高蔗糖西式饮食（high fat/sucrose Western diet, WD），可改变肝脏的基因组与翻译组谱，并伴随蛋白激酶mTORC1（protein kinase mTORC1）信号通路的活性变化，且此类改变与非酒精性脂肪性肝病（non-alcoholic fatty liver disease, NAFLD）的发生发展相关。
研究结果显示，相较于饲喂对照饮食（control diet, CD）的大鼠，饲喂WD的大鼠肝脏中存在诸多mRNA的表达量及/或翻译水平发生改变。具体而言，WD饲喂可改变参与脂质、脂肪酸代谢以及糖代谢、胰岛素信号通路相关mRNA的丰度及其核糖体结合情况。
当大鼠经整夜禁食后于晨间复饲时，肝脏mTORC1信号通路活性被增强；但相较于CD饲喂组，WD饲喂组的这一效应被显著削弱。尽管两组大鼠的血浆胰岛素浓度无显著差异，但WD饲喂组大鼠肝脏内的脂肪酸含量显著高于CD组。
我们发现，复饲可显著正向调控49种与肝脂肪变性相关的mRNA的核糖体占用率（例如LIPE、LPL），但该效应在WD饲喂组大鼠的肝脏中被抑制。在多数情况下，核糖体结合情况的变化与mRNA丰度的改变无关，这提示饮食诱导的mRNA翻译变化在对应mRNA编码蛋白的表达过程中发挥关键作用。
综上，本研究结果表明，短期饲喂WD不仅通过改变大量mRNA的丰度影响肝脏基因表达，还可引发广泛的mRNA翻译水平变化，这些变化或共同参与肝脂肪变性的发生发展。