THESIS
2020
ix, 78 pages : color illustrations ; 30 cm
Abstract
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.
Post a Comment