Loss-of-function (LOF) mutations in ANGPTL3, an inhibitor of lipoprotein lipase (LPL), cause a drastic reduction of serum lipoproteins and protect against the development of atherosclerotic cardiovascular disease. Therefore, ANGPTL3 is a promising therapy target. We characterized the impacts of ANGPTL3 depletion on the immortalized human hepatocyte (IHH) transcriptome, lipidome and human plasma lipoprotein lipidome. The transcriptome of ANGPTL3 knock-down (KD) cells showed altered expression of several pathways related to lipid metabolism. Accordingly, ANGPTL3 depleted IHH displayed changes in cellular overall fatty acid (FA) composition and in the lipid species composition of several lipid classes, characterized by abundant n-6 and n-3 polyunsaturated FAs (PUFAs). This PUFA increase coincided with an elevation of lipid mediators, among which there were species relevant for resolution of inflammation, protection from lipotoxic and hypoxia-induced ER stress, hepatic steatosis and insulin resistance or for the recovery from cardiovascular events. Cholesterol esters were markedly reduced in ANGPTL3 KD IHH, coinciding with suppression of the SOAT1 mRNA and protein. ANGPTL3 LOF caused alterations in plasma lipoprotein FA and lipid species composition. All lipoprotein fractions of the ANGPTL3 LOF subjects displayed a marked drop of 18:2n-6, while several highly unsaturated triacylglycerol (TAG) species were enriched. The present work reveals distinct impacts of ANGPTL3 depletion on the hepatocellular lipidome, transcriptome and lipid mediators, as well as on the lipidome of lipoproteins isolated from plasma of ANGPTL3-deficient human subjects. It is important to consider these lipidomics and transcriptomics findings when targeting ANGPTL3 for therapy and translating it to the human context.

中文翻译：

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ANGPTL3 缺乏会改变培养的肝细胞和人类脂蛋白的脂质谱和代谢。

脂蛋白脂肪酶 (LPL) 抑制剂 ANGPTL3 中的功能丧失 (LOF) 突变导致血清脂蛋白急剧减少并防止动脉粥样硬化心血管疾病的发展。因此，ANGPTL3 是一个很有前景的治疗靶点。我们描述了 ANGPTL3 耗竭对永生化人肝细胞 (IHH) 转录组、脂质组和人血浆脂蛋白脂质组的影响。ANGPTL3 敲低 (KD) 细胞的转录组显示与脂质代谢相关的几种途径的表达改变。因此，ANGPTL3 耗尽的 IHH 显示出细胞整体脂肪酸 (FA) 组成和几种脂质类别的脂质种类组成的变化，其特征在于丰富的 n-6 和 n-3 多不饱和脂肪酸 (PUFA)。这种 PUFA 的增加与脂质介质的升高同时发生，其中有与炎症消退、防止脂毒性和缺氧引起的内质网应激、肝脂肪变性和胰岛素抵抗或心血管事件恢复相关的物种。ANGPTL3 KD IHH 中的胆固醇酯显着减少，与 SOAT1 mRNA 和蛋白质的抑制一致。ANGPTL3 LOF 引起血浆脂蛋白 FA 和脂质种类组成的改变。ANGPTL3 LOF 受试者的所有脂蛋白组分均显示出 18:2n-6 的显着下降，同时富含多种高度不饱和甘油三酯 (TAG)。目前的工作揭示了 ANGPTL3 耗竭对肝细胞脂质组、转录组和脂质介质以及从 ANGPTL3 缺陷人类受试者血浆中分离的脂蛋白脂质组的明显影响。