AIDA Selectively Mediates Downregulation of Fat Synthesis Enzymes by ERAD to Retard Intestinal Fat Absorption and Prevent Obesity
AIDA Selectively Mediates Downregulation of Fat Synthesis Enzymes by ERAD to Retard Intestinal Fat Absorption and Prevent Obesity
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AIDA 通过 ERAD 选择性介导脂肪合成酶的下调，以延缓肠道脂肪吸收并预防肥胖
DOI：
10.1016/j.cmet.2018.02.021
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发表时间：
2018-04-03
期刊：
影响因子：
29
通讯作者：
Lin, Sheng-Cai
中科院分区：
文献类型：
--
作者：
Luo, Hui;Jiang, Ming;Lin, Sheng-Cai
膳食脂肪的肠道吸收效率构成了个体易患肥胖症的主要决定因素。然而，脂肪吸收是如何被控制并导致肥胖的仍然不清楚。在这里，我们表明，抑制内质网相关的降解（ERAD）增加了丰富的三酰甘油合成酶和脂肪吸收的小肠。C2-结构域蛋白AIDA作为ERAD的E3-连接酶HRD 1下调限速酰基转移酶GPAT 3、MOGAT 2和DGAT 2的必需因子。Aida（-/-）小鼠在热中性条件下生长或喂食高脂饮食时，表现出肠脂肪酸再酯化、循环和组织三酰甘油增加，伴随着严重增加的肥胖而不增强脂肪生成。肠特异性敲除Aida在很大程度上表型模仿其全身敲除，强烈表明肠TAG合成增加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，该机制影响了肠道脂肪吸收和全身脂肪储存的酶。
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.