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Anterior gradient 2 increases long-chain fatty acid uptake via stabilizing FABP1 and facilitates lipid accumulation
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 f...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975708/ https://www.ncbi.nlm.nih.gov/pubmed/33767592 http://dx.doi.org/10.7150/ijbs.57099 |
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author | Wang, Yunqiu Jia, Mengqi Liang, Chuanjie Sheng, Nan Wang, Xiaodan Wang, Fang Luo, Yanhai Jiang, Jin Cai, Liangyu Niu, Huanmin Zhu, Deyu Nesa, Effat Un Young, Charles YF Yuan, Huiqing |
author_facet | Wang, Yunqiu Jia, Mengqi Liang, Chuanjie Sheng, Nan Wang, Xiaodan Wang, Fang Luo, Yanhai Jiang, Jin Cai, Liangyu Niu, Huanmin Zhu, Deyu Nesa, Effat Un Young, Charles YF Yuan, Huiqing |
author_sort | Wang, Yunqiu |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7975708 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-79757082021-03-24 Anterior gradient 2 increases long-chain fatty acid uptake via stabilizing FABP1 and facilitates lipid accumulation Wang, Yunqiu Jia, Mengqi Liang, Chuanjie Sheng, Nan Wang, Xiaodan Wang, Fang Luo, Yanhai Jiang, Jin Cai, Liangyu Niu, Huanmin Zhu, Deyu Nesa, Effat Un Young, Charles YF Yuan, Huiqing Int J Biol Sci Research Paper 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. Ivyspring International Publisher 2021-02-08 /pmc/articles/PMC7975708/ /pubmed/33767592 http://dx.doi.org/10.7150/ijbs.57099 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Wang, Yunqiu Jia, Mengqi Liang, Chuanjie Sheng, Nan Wang, Xiaodan Wang, Fang Luo, Yanhai Jiang, Jin Cai, Liangyu Niu, Huanmin Zhu, Deyu Nesa, Effat Un Young, Charles YF Yuan, Huiqing Anterior gradient 2 increases long-chain fatty acid uptake via stabilizing FABP1 and facilitates lipid accumulation |
title | Anterior gradient 2 increases long-chain fatty acid uptake via stabilizing FABP1 and facilitates lipid accumulation |
title_full | Anterior gradient 2 increases long-chain fatty acid uptake via stabilizing FABP1 and facilitates lipid accumulation |
title_fullStr | Anterior gradient 2 increases long-chain fatty acid uptake via stabilizing FABP1 and facilitates lipid accumulation |
title_full_unstemmed | Anterior gradient 2 increases long-chain fatty acid uptake via stabilizing FABP1 and facilitates lipid accumulation |
title_short | Anterior gradient 2 increases long-chain fatty acid uptake via stabilizing FABP1 and facilitates lipid accumulation |
title_sort | anterior gradient 2 increases long-chain fatty acid uptake via stabilizing fabp1 and facilitates lipid accumulation |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975708/ https://www.ncbi.nlm.nih.gov/pubmed/33767592 http://dx.doi.org/10.7150/ijbs.57099 |
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