SEIPIN Regulates Lipid Droplet Expansion and Adipocyte Development by Modulating the Activity of Glycerol-3-phosphate Acyltransferase.
SEIPIN Regulates Lipid Droplet Expansion and Adipocyte Development by Modulating the Activity of Glycerol-3-phosphate Acyltransferase.
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DOI：
10.1016/j.celrep.2016.10.037
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发表时间：
2016-11-01
期刊：
影响因子：
8.8
通讯作者：
Yang H
中科院分区：
文献类型：
--
作者：
Pagac M;Cooper DE;Qi Y;Lukmantara IE;Mak HY;Wu Z;Tian Y;Liu Z;Lei M;Du X;Ferguson C;Kotevski D;Sadowski P;Chen W;Boroda S;Harris TE;Liu G;Parton RG;Huang X;Coleman RA;Yang H
Berardinelli-Seip先天性脂肪营养不良2（BSCL 2）是由SEIPIN的功能缺失突变引起的，SEIPIN是一种与脂肪形成和脂滴扩张有关的蛋白质，但其分子功能仍然不清楚。在这里，我们确定物理和功能之间的相互作用SEIPIN和微粒体异构体的甘油-3-磷酸酰基转移酶（GPAT）在多种生物体。与对照相比，GPAT活性在SEIPIN缺陷细胞和组织中升高，并且GPAT动力学值改变。增加的GPAT活性似乎支持与SEIPIN损失相关的脂肪形成和异常脂滴形态的阻断。Gpat 3的过表达阻断了脂肪形成，而Gpat 3在SEIPIN缺陷的前脂肪细胞中的敲低部分恢复了分化。GPAT在酵母、前脂肪细胞和苍蝇唾液腺中的过度表达也形成了超大的脂滴。最后，药物抑制Seipin−/−小鼠前脂肪细胞中的GPAT部分恢复了脂肪形成。这些数据鉴定了SEIPIN作为微粒体GPAT的进化上保守的调节剂，并表明GPAT抑制剂可能用于治疗人BSCL 2患者。Pagac等人发现与Berardinelli-Seip先天性脂肪营养不良2相关的SEIPIN与微粒体甘油-3-磷酸酰基转移酶（GPAT）相互作用并影响其活性。增加的GPAT活性似乎是与SEIPIN损失相关的脂肪形成和异常脂滴形态学阻断的基础。
Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) is caused by loss-of-function mutations in SEIPIN, a protein implicated in both adipogenesis and lipid droplet expansion but whose molecular function remains obscure. Here, we identify physical and functional interactions between SEIPIN and microsomal isoforms of glycerol-3-phosphate acyltransferase (GPAT) in multiple organisms. Compared to controls, GPAT activity was elevated in SEIPIN-deficient cells and tissues and GPAT kinetic values were altered. Increased GPAT activity appears to underpin the block in adipogenesis and abnormal lipid droplet morphology associated with SEIPIN loss. Over-expression of Gpat3 blocked adipogenesis, and Gpat3 knockdown in SEIPIN-deficient preadipocytes partially restored differentiation. GPAT overexpression in yeast, preadipocytes, and fly salivary glands also formed supersized lipid droplets. Finally, pharmacological inhibition of GPAT in Seipin−/− mouse preadipocytes partially restored adipogenesis. These data identify SEIPIN as an evolutionarily conserved regulator of microsomal GPAT and suggest that GPAT inhibitors might be useful for the treatment of human BSCL2 patients. Pagac et al. find that SEIPIN, which has been linked to Berardinelli-Seip congenital lipodystrophy 2, interacts with microsomal glycerol-3-phosphate acyltransferase (GPAT) and influences its activity. Increased GPAT activity appears to underlie the block in adipogenesis and abnormal lipid droplet morphology associated with SEIPIN loss.
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影响因子：
2.9
作者：
Binns D;Lee S;Hilton CL;Jiang QX;Goodman JM
通讯作者：
Goodman JM
DOI：
10.1152/ajpendo.00666.2013
发表时间：
2014-05-01
影响因子：
5.1
作者：
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通讯作者：
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影响因子：
56.9
作者：
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通讯作者：
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DOI：
10.1083/jcb.201502070
发表时间：
2015-11-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Grippa A;Buxó L;Mora G;Funaya C;Idrissi FZ;Mancuso F;Gomez R;Muntanyà J;Sabidó E;Carvalho P
通讯作者：
Carvalho P
影响因子：
64.8
作者：
Fu, Suneng;Yang, Ling;Li, Ping;Hofmann, Oliver;Dicker, Lee;Hide, Winston;Lin, Xihong;Watkins, Steven M.;Ivanov, Alexander R.;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.