title: Towards a mechanistic understanding of lipodystrophy and seipin functions.
abstract: CGL (Congenital generalized lipodystrophy) is a genetic disorder characterized by near complete loss of adipose tissue along with increased ectopic fat storage in other organs including liver and muscle. Of the four CGL types, BSCL2 (Berardinelli-Seip Congenital lipodystrophy type 2), resulting from mutations in the BSCL2/seipin gene, exhibits the most severe lipodystrophic phenotype with loss of both metabolic and mechanical adipose depots. The majority of Seipin mutations cause C-terminal truncations, along with a handful of point mutations. Seipin localizes to the ER and is composed of a conserved region including a luminal loop and two transmembrane domains, plus cytosolic N- and C-termini. Animal models deficient in seipin recapitulate the human lipodystrophic phenotype. Cells isolated from seipin knockout mouse models also exhibit impaired adipogenesis. Mechanistically, seipin appears to function as a scaffolding protein to bring together interacting partners essential for lipid metabolism and LD (lipid droplet) formation during adipocyte development. Moreover, cell line and genetic studies indicate that seipin functions in a cell-autonomous manner. Here we will provide a brief overview of the genetic association of the CGLs, and focus on the current understanding of differential contributions of distinct seipin domains to lipid storage and adipogenesis. We will also discuss the roles of seipin-interacting partners, including lipin 1 and 14-3-3β, in mediating seipin-dependent regulation of cellular pathways such as actin cytoskeletal remodelling.
authors.affiliation: *Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Wee
authors.affiliation: *Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Wulin
authors.initials: W
authors.lastname: Yang
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sugii
authors.forename: Weiping
authors.initials: W
authors.lastname: Han
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D050156:Adipogenesis; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D052497:Lipodystrophy, Congenital Generalized / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary
chemical_list: D048948:14-3-3 Proteins; C432679:BSCL2 protein, human; C115783:Bscl2 protein, mouse; D044388:GTP-Binding Protein gamma Subunits; D009687:Nuclear Proteins; C482982:YWHAB protein, human; C485999:LPIN1 protein, human; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase; D020962:Heterotrimeric GTP-Binding Proteins