Lipid synthesis and storage in human metabolic disorders

H Yang

UNSW, Sydney, Australia

Obesity is characterized by accumulation of adipocytes loaded with lipid droplets (LDs). By genetic screening in yeast, we identified a large number of gene products that regulate the size and number of LDs. In particular, we demonstrate that deletion of a previously uncharacterized gene, FLD1, results in the formation of “super-sized” LDs (>50 times the volume of normal ones). Interestingly, null mutations of SEIPIN (the human orthologue of Fld1p) are associated with human Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2). We use mouse and fly models to confirm an essential role of SEIPIN in adipogenesis. Therefore, SEIPIN regulates two important aspects of lipid storage: adipocyte differentiation (systemic lipid storage) and lipid droplet formation (cellular lipid storage). Our recent results suggest that SEIPIN functions in the metabolism of phospholipids, and that SEIPIN deficiency causes accumulation of certain lipid species, such as phosphatidic acid. These accumulated lipids may interfere with PPARgamma function during adipocyte differentiation, causing severe lipodystrophy. These lipid species may also cause morphological changes of LDs, e.g. the formation of “supersized” LDs, in other cell types. These findings may lead to novel therapeutic strategies against human congenital generalized lipodystrophies.