Anterior gradient 2 increases long-chain fatty acid uptake via stabilizing FABP1 and facilitates lipid accumulation.
Anterior gradient 2 increases long-chain fatty acid uptake via stabilizing FABP1 and facilitates lipid accumulation.
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前梯度 2 通过稳定 FABP1 增加长链脂肪酸摄取并促进脂质积累
DOI：
10.7150/ijbs.57099
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发表时间：
2021
影响因子：
9.2
通讯作者：
Yuan H
中科院分区：
文献类型：
--
作者：
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 CY;Yuan H
前梯度 2 (AGR2) 是一种蛋白质二硫键异构酶 (PDI)，是一种公认的癌基因。在这里，我们发现 Agr2-/- 小鼠与野生型同窝小鼠相比，禁食后脂肪量、肝脏和血清脂质水平降低，并且高脂饮食 (HFD) 诱导的脂肪积累减少。过度表达 AGR2 (Agr2/Tg) 的转基因小鼠在食用 HFD 后很容易增加脂肪重量，但正常饮食则不然。对 Agr2-/- 小鼠肝脏样本的蛋白质组学分析表明，AGR2 的缺失会损害长链脂肪酸的摄取和激活，但不会影响肝脏脂肪生成。进一步的研究确定了几种效应底物，特别是脂肪酸结合蛋白 1 (FABP1)，它对于 AGR2 介导的作用至关重要。 AGR2 与 FABP1 共表达，AGR2 的敲除导致 FABP1 稳定性降低。 AGR2 和 FABP1 的物理相互作用取决于 AGR2 中的 PDI 基序以及这两种蛋白质之间二硫键的形成。 AGR2 的过表达（而非缺乏 PDI 活性的突变 AGR2 蛋白）抑制了缺乏 FABP1 的细胞中的脂质积累。此外，AGR2缺陷显着降低了肠道的脂肪酸吸收，这可能是由于小鼠体内脂肪酸转运蛋白CD36减少所致。这些发现证明了AGR2在肝脏和肠道的脂肪酸摄取和激活中的新作用，这有助于AGR2介导的脂质积累，表明AGR2是全身脂质代谢的重要调节因子，AGR2的下调可能会拮抗肥胖的发展。
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.
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影响因子：
3.4
作者：
Bechtel TJ;Weerapana E
通讯作者：
Weerapana E
影响因子：
29
作者：
Roqueta-Rivera M;Esquejo RM;Phelan PE;Sandor K;Daniel B;Foufelle F;Ding J;Li X;Khorasanizadeh S;Osborne TF
通讯作者：
Osborne TF
蛋白质二硫键异构酶 AGR2 对于肠粘液的产生至关重要
DOI：
10.1073/pnas.0808722106
发表时间：
2009-04-28
影响因子：
11.1
作者：
Park, Sung-Woo;Zhen, Guohua;Erle, David J.
通讯作者：
Erle, David J.
DOI：
10.1016/j.plefa.2010.02.029
发表时间：
2010-04-01
影响因子：
3
作者：
Schwenk, Robert W.;Holloway, Graham P.;Glatz, Jan F. C.
通讯作者：
Glatz, Jan F. C.
影响因子：
2.4
作者：
Park, Christine J.;Armenia, Sarah J.;Cowles, Robert A.
通讯作者：
Cowles, Robert A.