title: Seipin deficiency alters fatty acid Delta9 desaturation and lipid droplet formation in Berardinelli-Seip congenital lipodystrophy.
abstract: Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare recessive disease characterized by near absence of adipose tissue and severe insulin resistance. In most cases, BSCL is due to loss-of-function mutations in the genes encoding either seipin of unknown function or 1-acyl-glycerol-3-phosphate O-acyltransferase 2 (AGPAT2) which catalyses the formation of phosphatidic acid from lysophosphatidic acid. We studied the lipid profile of lymphoblastoid cell-lines from 20 BSCL patients with null mutations in the genes encoding either seipin (n=12) or AGPAT2 (n=8) in comparison to nine control cell-lines. In seipin deficient cells, we observed alterations in the pattern of lipid droplets which were decreased in size and increased in number as compared to control cells. We also observed alterations in the triglycerides content as well as in the fatty acid composition from triglycerides and phosphatidylethanolamine, with an increased proportion of saturated fatty acids at the expense of the corresponding monounsaturated fatty acids, reflecting a defect in Delta9-desaturase activity. In AGPAT2 deficient cells, no specific alterations in lipid droplet pattern nor in fatty acid composition was observed but the cellular level of lysophosphatidic acid was increased as compared to that of control and seipin deficient cells. These results indicate that seipin like AGPAT2 is involved in lipid metabolism but exerts a different function. Seipin intervenes at a proximal step in triglycerides and phospholipids biosynthesis being involved in the pathway that links fatty acid Delta9 desaturation to lipid droplet formation. These findings provide new insights into how seipin deficiency causes severe lipodystrophy.
authors.affiliation: INSERM, UMR, CDR Saint-Antoine, Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Boutet
authors.forename: Haquima
authors.initials: H
authors.lastname: El Mourabit
authors.forename: Matthieu
authors.initials: M
authors.lastname: Prot
authors.forename: Mona
authors.initials: M
authors.lastname: Nemani
authors.forename: Eliane
authors.initials: E
authors.lastname: Khallouf
authors.forename: Odile
authors.initials: O
authors.lastname: Colard
authors.forename: Michèle
authors.initials: M
authors.lastname: Maurice
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Durand-Schneider
authors.forename: Yves
authors.initials: Y
authors.lastname: Chrétien
authors.forename: Sandra
authors.initials: S
authors.lastname: Grès
authors.forename: Claude
authors.initials: C
authors.lastname: Wolf
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Saulnier-Blache
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Magré
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002461:Cell Line, Transformed; D002648:Child; D002675:Child, Preschool; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D044388:GTP-Binding Protein gamma Subunits / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D050356:Lipid Metabolism; D008055:Lipids / Q000032:analysis / Q000737:chemistry; D052497:Lipodystrophy, Congenital Generalized / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D055815:Young Adult
chemical_list: C432679:BSCL2 protein, human; D005231:Fatty Acids, Unsaturated; D044388:GTP-Binding Protein gamma Subunits; D008055:Lipids; D012333:RNA, Messenger; D014280:Triglycerides; D013230:Stearoyl-CoA Desaturase; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase