Lipodystrophy is a metabolic disorder characterized by the loss of adipose tissue. Lipodystrophic patients often suffered from severe hepatic steatosis and diabetes-related symptoms such as hypertriglyceridemia and insulin resistance. Congenital Generalized Lipodystrophy Type 2 disease (CGL2) is one of the most severe inherited forms of lipodystrophy in humans. This autosomal recessive syndrome is caused by mutations in the BSCL2 gene that encodes an ER membrane protein called seipin. Recent studies have demonstrated the importance of seipin in regulating lipid storage and adipogenesis. Yet, the detailed cellular and molecular mechanisms by which seipin is involved remain obscure.

Here, we report that the C. elegans seipin ortholog SEIP-1 is enriched in membrane tubular cages...[ Read more ]

Lipodystrophy is a metabolic disorder characterized by the loss of adipose tissue. Lipodystrophic patients often suffered from severe hepatic steatosis and diabetes-related symptoms such as hypertriglyceridemia and insulin resistance. Congenital Generalized Lipodystrophy Type 2 disease (CGL2) is one of the most severe inherited forms of lipodystrophy in humans. This autosomal recessive syndrome is caused by mutations in the BSCL2 gene that encodes an ER membrane protein called seipin. Recent studies have demonstrated the importance of seipin in regulating lipid storage and adipogenesis. Yet, the detailed cellular and molecular mechanisms by which seipin is involved remain obscure.

Here, we report that the C. elegans seipin ortholog SEIP-1 is enriched in membrane tubular cages around a subset of lipid droplets (LDs) in both the soma and germline. Dysfunction of SEIP-1 impairs intracellular lipid storage and causes embryonic arrest. Using site-directed mutagenesis, we have identified specific residues that are necessary for the proper targeting and function of SEIP-1. Of note, worms carrying an A185P missense mutation in SEIP-1, which is analogous to a lipodystrophy-associated mutation (A212P) in human seipin, showed phenotypes similar to the null mutant. From a forward genetic screen, we have successfully identified two classes of suppressor alleles that alleviate seip-1 deficiency. Molecular cloning of these suppressors may help reveal novel therapeutic targets that can be manipulated for treating seipin-related lipodystrophy.