SEIPIN Regulates Lipid Droplet Expansion and Adipocyte Development by Modulating the Activity of Glycerol-3-phosphate Acyltransferase.
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.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Martin
M
Pagac
Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA.
Daniel E
DE
Cooper
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Yanfei
Y
Qi
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Ivan E
IE
Lukmantara
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Hoi Yin
HY
Mak
Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA.
Zengying
Z
Wu
State Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
Yuan
Y
Tian
State Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
Zhonghua
Z
Liu
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Mona
M
Lei
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Ximing
X
Du
Institute for Molecular Bioscience, The University of Queensland, Queensland, QLD 4072, Australia.
Charles
C
Ferguson
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Damian
D
Kotevski
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Pawel
P
Sadowski
Department of Physiology, Medical College of Georgia Regents University, Augusta, GA 30912, USA.
Weiqin
W
Chen
Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
Salome
S
Boroda
Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
Thurl E
TE
Harris
Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
George
G
Liu
Institute for Molecular Bioscience, The University of Queensland, Queensland, QLD 4072, Australia.
Robert G
RG
Parton
State Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
Xun
X
Huang
Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA.
Rosalind A
RA
Coleman
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: h.rob.yang@unsw.edu.au.
Hongyuan
H
Yang
D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism*; D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D004330:Drosophila / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D066292:Lipid Droplets / Q000187:drug effects / Q000378:metabolism*; D008322:Mammals / Q000378:metabolism; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000378:metabolism
C432679:BSCL2 protein, human; C115783:Bscl2 protein, mouse; D004791:Enzyme Inhibitors; D044388:GTP-Binding Protein gamma Subunits; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D020962:Heterotrimeric GTP-Binding Proteins
AGPAT2; BSCL1; BSCL2; GPAT3; GPAT4; SEIPIN; adipogenesis; lipid droplets; lipodystrophy; phosphatidic acid