State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Cell Metab. 2018 Apr 3;27(4):843-853.e6. doi: 10.1016/j.cmet.2018.02.021.
The efficiency of intestinal absorption of dietary fat constitutes a primary determinant accounting for individual vulnerability to obesity. However, how fat absorption is controlled and contributes to obesity remains unclear. Here, we show that inhibition of endoplasmic-reticulum-associated degradation (ERAD) increases the abundance of triacylglycerol synthesis enzymes and fat absorption in small intestine. The C2-domain protein AIDA acts as an essential factor for the E3-ligase HRD1 of ERAD to downregulate rate-limiting acyltransferases GPAT3, MOGAT2, and DGAT2. Aida mice, when grown in a thermal-neutral condition or fed high-fat diet, display increased intestinal fatty acid re-esterification, circulating and tissue triacylglycerol, accompanied with severely increased adiposity without enhancement of adipogenesis. Intestine-specific knockout of Aida largely phenocopies its whole-body knockout, strongly indicating that increased intestinal TAG synthesis is a primary impetus to obesity. The AIDA-mediated ERAD system may thus represent an anti-thrifty mechanism impinging on the enzymes for intestinal fat absorption and systemic fat storage.
膳食脂肪的肠道吸收效率是导致个体肥胖易感性的主要决定因素。然而，脂肪吸收是如何被控制的，以及它如何导致肥胖，目前仍不清楚。在这里，我们发现内质网相关降解（ERAD）的抑制会增加甘油三酯合成酶的丰度，并增加小肠的脂肪吸收。C2 结构域蛋白 AIDA 作为 ERAD 的 E3 连接酶 HRD1 的必需因子，下调限速酰基转移酶 GPAT3、MOGAT2 和 DGAT2。在热中性条件下生长或喂食高脂肪饮食的 Aida 小鼠，表现出增加的肠道脂肪酸再酯化、循环和组织三酰基甘油，伴随着严重的肥胖增加，而脂肪生成没有增强。Aida 的肠道特异性敲除在很大程度上模拟了其全身敲除，强烈表明增加的肠道 TAG 合成是肥胖的主要推动力。因此，AIDA 介导的 ERAD 系统可能代表了一种抗节俭机制，影响肠道脂肪吸收和全身脂肪储存的酶。
