Int J Biol Sci 2021; 17(3):834-847. doi:10.7150/ijbs.57099

Research Paper

Anterior gradient 2 increases long-chain fatty acid uptake via stabilizing FABP1 and facilitates lipid accumulation

Yunqiu Wang1,2, Mengqi Jia1, Chuanjie Liang1,2, Nan Sheng1, Xiaodan Wang1, Fang Wang1, Yanhai Luo1,2, Jin Jiang1, Liangyu Cai1, Huanmin Niu1, Deyu Zhu2, Effat Un Nesa1, Charles YF Young3, Huiqing Yuan1,2✉

1. Key Laboratory of Experimental Teratology of Ministry of Education, Institute of Medical Sciences, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China.
2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250014, China.
3. Department of Urology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester 55905, MN, USA.

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Citation:
Wang Y, Jia M, Liang C, Sheng N, Wang X, Wang F, Luo Y, Jiang J, Cai L, Niu H, Zhu D, Nesa EU, Young CYF, Yuan H. Anterior gradient 2 increases long-chain fatty acid uptake via stabilizing FABP1 and facilitates lipid accumulation. Int J Biol Sci 2021; 17(3):834-847. doi:10.7150/ijbs.57099. Available from https://www.ijbs.com/v17p0834.htm

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Abstract

Anterior gradient 2 (AGR2), a protein disulfide isomerase (PDI), is a well-established oncogene. Here, we found that Agr2-/- mice had a decreased fat mass and hepatic and serum lipid levels compared with their wild-type littermates after fasting, and exhibited reduced high-fat diet (HFD)-induced fat accumulation. Transgenic mice overexpressing AGR2 (Agr2/Tg) readily gained fat weight on a HFD but not a normal diet. Proteomic analysis of hepatic samples from Agr2-/- mice revealed that depletion of AGR2 impaired long-chain fatty acid uptake and activation but did not affect de novo hepatic lipogenesis. Further investigations led to the identification of several effector substrates, particularly fatty acid binding protein-1 (FABP1) as essential for the AGR2-mediated effects. AGR2 was coexpressed with FABP1, and knockdown of AGR2 resulted in a reduction in FABP1 stability. Physical interactions of AGR2 and FABP1 depended on the PDI motif in AGR2 and the formation of a disulfide bond between these two proteins. Overexpression of AGR2 but not a mutant AGR2 protein lacking PDI activity suppressed lipid accumulation in cells lacking FABP1. Moreover, AGR2 deficiency significantly reduced fatty acid absorption in the intestine, which might be resulted from decreased fatty acid transporter CD36 in mice. These findings demonstrated a novel role of AGR2 in fatty-acid uptake and activation in both the liver and intestine, which contributed to the AGR2-mediated lipid accumulation, suggesting that AGR2 is an important regulator of whole-body lipid metabolism and down-regulation of AGR2 may antagonize the development of obesity.

Keywords: AGR2, lipid metabolism, chaperone, FABP1, liver, intestine