AIDA Selectively Mediates Downregulation of Fat Synthesis Enzymes by ERAD to Retard Intestinal Fat Absorption and Prevent Obesity

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 degrada...

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Bibliographic Details
Published in:	Cell metabolism 2018-04, Vol.27 (4), p.843-853.e6
Main Authors:	Luo, Hui, Jiang, Ming, Lian, Guili, Liu, Qing, Shi, Meng, Li, Terytty Yang, Song, Lintao, Ye, Jing, He, Ying, Yao, Luming, Zhang, Cixiong, Lin, Zhi-Zhong, Zhang, Chen-Song, Zhao, Tong-Jin, Jia, Wei-Ping, Li, Peng, Lin, Shu-Yong, Lin, Sheng-Cai
Format:	Article
Language:	eng
Subjects:	AIDA DGAT2 ER-associated degradation fat absorption fat storage GPAT3 HRD1 MOGAT2 triacylglycerol synthesis
Online Access:	Get full text
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Summary:	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. [Display omitted] •Increased fat absorption acts as a primary impetus to systemic fat storage•Aida knockout increases intestinal fatty acid re-esterification and fat absorption•AIDA is a regulatory component of the ER-associated degradation (ERAD)•AIDA selectively enhances ERAD to target triacylglycerol synthesis enzymes How fat is absorbed in the intestine and contributes to obesity is not well understood. Here, Luo et al. show that the ERAD-pathway protein AIDA downregulates triacylglycerol synthesis rate-limiting enzymes in the small intestine by enhancing their degradation. Deficiency of AIDA leads to increased intestinal fat absorption and severe obesity.
ISSN:	1550-4131 1932-7420