SEIPIN regulates lipid droplet expansion and adipocyte development by modulating the activity of glycerol-3-phosphate acyltransferase

Pagac, Martin, Cooper, Daniel E., Qi, Yanfei, Lukmantara, Ivan E., Mak, Hoi Yin, Wu, Zengying, Tian, Yuan, Liu, Zhonghua, Lei, Mona, Du, Ximing, Ferguson, Charles, Kotevski, Damian, Sadowski, Pawel, Chen, Weiqin, Boroda, Salome, Harris, Thurl E., Liu, George, Parton, Robert G., Huang, Xun, Coleman, Rosalind A. and Yang, Hongyuan (2016) SEIPIN regulates lipid droplet expansion and adipocyte development by modulating the activity of glycerol-3-phosphate acyltransferase. Cell Reports, 17 6: 1546-1559. doi:10.1016/j.celrep.2016.10.037


Author Pagac, Martin
Cooper, Daniel E.
Qi, Yanfei
Lukmantara, Ivan E.
Mak, Hoi Yin
Wu, Zengying
Tian, Yuan
Liu, Zhonghua
Lei, Mona
Du, Ximing
Ferguson, Charles
Kotevski, Damian
Sadowski, Pawel
Chen, Weiqin
Boroda, Salome
Harris, Thurl E.
Liu, George
Parton, Robert G.
Huang, Xun
Coleman, Rosalind A.
Yang, Hongyuan
Title SEIPIN regulates lipid droplet expansion and adipocyte development by modulating the activity of glycerol-3-phosphate acyltransferase
Journal name Cell Reports   Check publisher's open access policy
ISSN 2211-1247
Publication date 2016-11-01
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.celrep.2016.10.037
Open Access Status DOI
Volume 17
Issue 6
Start page 1546
End page 1559
Total pages 14
Place of publication New York, NY, United States
Publisher Elsevier
Language eng
Abstract 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.
Formatted abstract
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.
Keyword AGPAT2
BSCL1
BSCL2
GPAT3
GPAT4
SEIPIN
adipogenesis
lipid droplets
lipodystrophy
phosphatidic acid
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01 DK056598
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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