Dietary lipids are taken up as FAs by the intestinal epithelium and converted by diacylglycerol acyltransferase (DGAT) enzymes into triglycerides, which are packaged in chylomicrons or stored in cytoplasmic lipid droplets (LDs). DGAT1-deficient patients suffer from vomiting, diarrhea, and protein losing enteropathy, illustrating the importance of this process to intestinal homeostasis. Previously, we have shown that DGAT1 deficiency causes decreased LD formation and resistance to unsaturated FA lipotoxicity in patient-derived intestinal organoids. However, LD formation was not completely abolished in patient-derived organoids, suggesting the presence of an alternative mechanism for LD formation. Here, we show an unexpected role for DGAT2 in lipid metabolism, as DGAT2 partially compensates for LD formation and lipotoxicity in DGAT1-deficient intestinal stem cells. Furthermore, we show that (un)saturated FA-induced lipotoxicity is mediated by ER stress. More importantly, we demonstrate that overexpression of DGAT2 fully compensates for the loss of DGAT1 in organoids, indicating that induced DGAT2 expression in patient cells may serve as a therapeutic target in the future.

中文翻译：

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DGAT2 部分补偿了人 DGAT1 缺陷型肠道干细胞中脂质诱导的内质网应激。

膳食脂质被肠上皮吸收为 FA，并通过二酰基甘油酰基转移酶 (DGAT) 转化为甘油三酯，甘油三酯被包装在乳糜微粒中或储存在细胞质脂滴 (LD) 中。DGAT1 缺陷患者会出现呕吐、腹泻和蛋白质丢失性肠病，说明这一过程对肠道稳态的重要性。以前，我们已经表明 DGAT1 缺乏导致患者来源的肠道类器官中 LD 形成减少和对不饱和脂肪酸脂毒性的抵抗。然而，患者来源的类器官中的 LD 形成并未完全消除，这表明存在 LD 形成的替代机制。在这里，我们展示了 DGAT2 在脂质代谢中的意外作用，因为 DGAT2 部分补偿了 DGAT1 缺陷肠干细胞中的 LD 形成和脂毒性。此外，我们表明（不）饱和 FA 诱导的脂毒性是由内质网应激介导的。更重要的是，我们证明 DGAT2 的过表达完全补偿了类器官中 DGAT1 的缺失，表明患者细胞中诱导的 DGAT2 表达可能在未来作为治疗靶点。