SEIPIN Regulates Lipid Droplet Expansion and Adipocyte Development by Modulating the Activity of Glycerol-3-phosphate Acyltransferase

被引：144

作者：

Pagac, Martin ^{[1
]}

Cooper, Daniel E. ^{[2
]}

Qi, Yanfei ^{[1
]}

Lukmantara, Ivan E. ^{[1
]}

Mak, Hoi Yin ^{[1
]}

Wu, Zengying ^{[2
]}

Tian, Yuan ^{[3
]}

Liu, Zhonghua ^{[3
]}

Lei, Mona ^{[1
]}

Du, Ximing ^{[1
]}

Ferguson, Charles ^{[4
]}

Kotevski, Damian ^{[1
]}

Sadowski, Pawel ^{[1
,9
]}

Chen, Weiqin ^{[5
]}

Boroda, Salome ^{[6
]}

Harris, Thurl E. ^{[6
]}

Liu, George ^{[7
,8
]}

Parton, Robert G. ^{[4
]}

Huang, Xun

Coleman, Rosalind A. ^{[2
]}

Yang, Hongyuan ^{[1
]}

机构：

[1] Univ New South Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia

[2] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA

[3] Chinese Acad Sci, Inst Genet & Dev Biol, State Key Lab Mol & Dev Biol, Beijing 100101, Peoples R China

[4] Univ Queensland, Inst Mol Biosci, Queensland, Qld 4072, Australia

[5] Georgia Regents Univ, Coll Med, Dept Physiol, Augusta, GA 30912 USA

[6] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA

[7] Peking Univ, Hlth Sci Ctr, Minist Educ, Inst Cardiovasc Sci, Beijing 100191, Peoples R China

[8] Peking Univ, Hlth Sci Ctr, Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing 100191, Peoples R China

[9] Queensland Univ Technol, Inst Future Environm, Brisbane, Qld 4000, Australia

来源：

CELL REPORTS | 2016年 / 17卷 / 06期

基金：

英国医学研究理事会; 澳大利亚研究理事会;

关键词：

LIPODYSTROPHY PROTEIN SEIPIN; PHOSPHATIDIC-ACID; ADIPOSE-TISSUE; TRIACYLGLYCEROL SYNTHESIS; CONGENITAL LIPODYSTROPHY; METABOLISM; YEAST; ADIPOGENESIS; MICE; HOMEOSTASIS;

D O I：

10.1016/j.celrep.2016.10.037

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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. Overexpression 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.

引用

页码：1546 / 1559

页数：14

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