Population genetic studies highlight a missense variant (G398S) of A1CF that is strongly associated with higher levels of blood triglycerides (TGs) and total cholesterol (TC). Functional analyses suggest that the mutation accelerates the secretion of very low-density lipoprotein (VLDL) from the liver by an unknown mechanism. Here, we used multiomics approaches to interrogate the functional difference between the WT and mutant A1CF. Using metabolomics analyses, we captured the cellular lipid metabolite changes induced by transient expression of the proteins, confirming that the mutant A1CF is able to relieve the TG accumulation induced by WT A1CF. Using a proteomics approach, we obtained the interactomic data of WT and mutant A1CF. Networking analyses show that WT A1CF interacts with three functional protein groups, RNA/mRNA processing, cytosolic translation, and, surprisingly, mitochondrial translation. The mutation diminishes these interactions, especially with the group of mitochondrial translation. Differential analyses show that the WT A1CF-interacting proteins most significantly different from the mutant are those for mitochondrial translation, whereas the most significant interacting proteins with the mutant are those for cytoskeleton and vesicle-mediated transport. RNA-seq analyses validate that the mutant, but not the WT, A1CF increases the expression of the genes responsible for cellular transport processes. On the contrary, WT A1CF affected the expression of mitochondrial matrix proteins and increased cell oxygen consumption. Thus, our studies confirm the previous hypothesis that A1CF plays broader roles in regulating gene expression. The interactions of the mutant A1CF with the vesicle-mediated transport machinery provide mechanistic insight in understanding the increased VLDL secretion in the A1CF mutation carriers.

中文翻译：

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Interactomics分析野生型和突变的A1CF揭示了调节细胞脂质代谢的分散功能。

群体遗传学研究强调了A1CF的一个错义变异（G398S）与血液中甘油三酸酯（TGs）和总胆固醇（TC）的较高水平密切相关。功能分析表明，该突变通过未知机制加速了肝脏中非常低密度脂蛋白（VLDL）的分泌。在这里，我们使用了多组学方法来研究野生型和突变型A1CF之间的功能差异。使用代谢组学分析，我们捕获了蛋白质瞬时表达诱导的细胞脂质代谢产物变化，证实突变体A1CF能够缓解WT A1CF诱导的TG积累。使用蛋白质组学方法，我们获得了野生型和突变A1CF的相互作用组数据。网络分析表明，WT A1CF与三个功能蛋白组相互作用，RNA / mRNA加工，胞质翻译，以及令人惊讶的线粒体翻译。突变减少了这些相互作用，尤其是与线粒体翻译组的相互作用。差异分析显示，与突变体最显着不同的是与WT A1CF相互作用的蛋白质，是线粒体翻译的蛋白质，而与突变体最显着的相互作用的蛋白质是与细胞骨架和囊泡介导的转运蛋白。RNA-seq分析验证了该突变体而非野生型A1CF增加了负责细胞转运过程的基因的表达。相反，WT A1CF影响线粒体基质蛋白的表达并增加细胞耗氧量。因此，我们的研究证实了先前的假设，即A1CF在调节基因表达中起着更广泛的作用。