SEIPIN Regulates Lipid Droplet Expansion and Adipocyte Development by Modulating the Activity of Glycerol-3-phosphate Acyltransferase
| Autor: | Damian P Kotevski, Zengying Wu, Weiqin Chen, Yuan Tian, Ivan Lukmantara, Yanfei Qi, Hongyuan Yang, Mona Lei, Daniel E. Cooper, Robert G. Parton, George Liu, Martin Pagac, Thurl E. Harris, Zhonghua Liu, Xun Huang, Pawel Sadowski, Salome Boroda, Charles Ferguson, Hoi Yin Mak, Ximing Du, Rosalind A. Coleman |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
lipodystrophy BSCL2 Saccharomyces cerevisiae Article General Biochemistry Genetics and Molecular Biology Seipin SEIPIN Mice 03 medical and health sciences chemistry.chemical_compound GPAT3 0302 clinical medicine GPAT4 3T3-L1 Cells GTP-Binding Protein gamma Subunits Adipocyte Lipid droplet Adipocytes Animals Humans Enzyme Inhibitors lcsh:QH301-705.5 Mammals Gene knockdown Adipogenesis Lipid Droplets Phosphatidic acid 1-Acylglycerol-3-Phosphate O-Acyltransferase Heterotrimeric GTP-Binding Proteins AGPAT2 phosphatidic acid Kinetics 030104 developmental biology lcsh:Biology (General) chemistry Biochemistry Acyltransferase BSCL1 Drosophila 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Cell reports Cell Reports, Vol 17, Iss 6, Pp 1546-1559 (2016) |
| DOI: | 10.17615/9r5p-ma05 |
| Popis: | SUMMARY 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. Over-expression 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. In Brief 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. |
| Databáze: | OpenAIRE |
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