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

• DOI: 10.1016/j.celrep.2016.10.037
• Publication Date: 2016-11-01T16:30:55Z
• Authors: 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. Coleman; Hongyuan Yang
• Keywords: 0301 basic medicine; lipodystrophy; 1300 Biochemistry; 572; QH301-705.5; lipid droplets; 610; Genetics and Molecular Biology; Saccharomyces cerevisiae; yeast; 3101 Biochemistry and Cell Biology; Article; SEIPIN; adipogenesis; Mice; 03 medical and health sciences; proteomics; GPAT3; GPAT4; 3T3-L1 Cells; GTP-Binding Protein gamma Subunits; 616; Adipocytes; 2.1 Biological and endogenous factors; Animals; Humans; anzsrc-for: 31 Biological Sciences; Biology (General); Enzyme Inhibitors; Mammals; 0303 health sciences; Adipogenesis; anzsrc-for: 3101 Biochemistry and Cell Biology; Lipid Droplets; 1-Acylglycerol-3-Phosphate O-Acyltransferase; Heterotrimeric GTP-Binding Proteins; AGPAT2; phosphatidic acid; Kinetics; BSCL; seipin; BSCL1; BSCL2; Drosophila; 31 Biological Sciences; Protein Binding

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.