Journal
CELL METABOLISM
Volume 27, Issue 4, Pages 843-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2018.02.021
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Funding
- National Key R&D Program of China [2016YFA0502000]
- 973 program of China [2014CB910602]
- National Natural Science Foundation of China [31430094, 31690101, 31571214]
- Fundamental Research Funds for the Central Universities [20720160058]
- XMU Training Program of Innovation and Enterpreneurship for Undergraduates [2017Y0569]
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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.
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