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

Martin Pagac, Daniel E. Cooper, Yanfei Qi, Ivan E. Lukmantara, Hoi Yin Mak, Zengying Wu, Yuan Tian, Zhonghua Liu, Mona Lei, Ximing Du, Charles Ferguson, Damian Kotevski, Pawel Sadowski, Weiqin Chen, Salome Boroda, Thurl E. Harris, George Liu, Robert G. Parton, Xun Huang, Rosalind A. ColemanHongyuan Yang

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1546-1559
Number of pages14
JournalCell Reports
Volume17
Issue number6
DOIs
StatePublished - Nov 1 2016

Fingerprint

Acyltransferases
Adipocytes
Lipids
Adipogenesis
Congenital Generalized Lipodystrophy
alpha-glycerophosphoric acid
Lipid Droplets
Yeast
Protein Isoforms
Yeasts
Pharmacology
Tissue
Mutation
Kinetics

Keywords

  • AGPAT2
  • BSCL1
  • BSCL2
  • GPAT3
  • GPAT4
  • SEIPIN
  • adipogenesis
  • lipid droplets
  • lipodystrophy
  • phosphatidic acid

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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.; Yang, Hongyuan.

In: Cell Reports, Vol. 17, No. 6, 01.11.2016, p. 1546-1559.

Research output: Contribution to journalArticle

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 2016, 'SEIPIN Regulates Lipid Droplet Expansion and Adipocyte Development by Modulating the Activity of Glycerol-3-phosphate Acyltransferase', Cell Reports, vol. 17, no. 6, pp. 1546-1559. https://doi.org/10.1016/j.celrep.2016.10.037
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. / SEIPIN Regulates Lipid Droplet Expansion and Adipocyte Development by Modulating the Activity of Glycerol-3-phosphate Acyltransferase. In: Cell Reports. 2016 ; Vol. 17, No. 6. pp. 1546-1559.
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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.",
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AU - Pagac, Martin

AU - Cooper, Daniel E.

AU - Qi, Yanfei

AU - Lukmantara, Ivan E.

AU - Mak, Hoi Yin

AU - Wu, Zengying

AU - Tian, Yuan

AU - Liu, Zhonghua

AU - Lei, Mona

AU - Du, Ximing

AU - Ferguson, Charles

AU - Kotevski, Damian

AU - Sadowski, Pawel

AU - Chen, Weiqin

AU - Boroda, Salome

AU - Harris, Thurl E.

AU - Liu, George

AU - Parton, Robert G.

AU - Huang, Xun

AU - Coleman, Rosalind A.

AU - Yang, Hongyuan

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N2 - 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.

AB - 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.

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