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

• Published in: Cell reports (Cambridge) Vol. 17; no. 6; pp. 1546 - 1559
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2016; Elsevier
• Subjects: 1-Acylglycerol-3-Phosphate O-Acyltransferase - metabolism; 3T3-L1 Cells; Adipocytes - drug effects; Adipocytes - metabolism; adipogenesis; Adipogenesis - drug effects; AGPAT2; Animals; BSCL1; BSCL2; Drosophila - metabolism; Enzyme Inhibitors - pharmacology; GPAT3; GPAT4; GTP-Binding Protein gamma Subunits - metabolism; Heterotrimeric GTP-Binding Proteins - deficiency; Heterotrimeric GTP-Binding Proteins - metabolism; Humans; Kinetics; lipid droplets; Lipid Droplets - drug effects; Lipid Droplets - metabolism; lipodystrophy; Mammals - metabolism; Mice; phosphatidic acid; Protein Binding - drug effects; Saccharomyces cerevisiae - metabolism; SEIPIN; BSCL2; adipogenesis; GPAT4; GPAT3; phosphatidic acid; lipid droplets; AGPAT2; SEIPIN; lipodystrophy; BSCL1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.10.037

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. [Display omitted] •Loss of SEIPIN function causes Berardinelli-Seip congenital lipodystrophy 2•Lack of SEIPIN increases glycerol-3-phosphate acyltransferase (GPAT) activity•Inhibiting GPAT enhances differentiation of SEIPIN-deficient preadipocytes•Inhibiting GPAT corrects abnormal lipid droplet morphology in SEIPIN deficiency Pagac et al. find that SEIPIN, which has been linked to Berardinelli-Seip congenital lipodystrophy 2, interacts with microsomal glycerol-3-phosphate acyltransferase (GPAT) and influences its activity. Increased GPAT activity appears to underlie the block in adipogenesis and abnormal lipid droplet morphology associated with SEIPIN loss.