Alleviation of seipinopathy-related ER stress by triglyceride storage
- Authors
- Holtta-Vuori, M., Salo, V.T., Ohsaki, Y., Suster, M.L., and Ikonen, E.
- ID
- ZDB-PUB-121221-9
- Date
- 2013
- Source
- Human molecular genetics 22(6): 1157-1166 (Journal)
- Registered Authors
- Suster, Maximiliano
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Line, Tumor
- Endoplasmic Reticulum/metabolism
- Endoplasmic Reticulum Stress*
- GTP-Binding Protein gamma Subunits/genetics
- GTP-Binding Protein gamma Subunits/metabolism
- Humans
- Lipodystrophy/genetics
- Lipodystrophy/metabolism*
- Triglycerides/metabolism*
- Zebrafish
- PubMed
- 23250914 Full text @ Hum. Mol. Genet.
Mutations affecting the N-glycosylation site in Berardinelli-Seip lipodystrophy associated gene BSCL2/seipin lead to a dominantly inherited spastic paraplegia termed seipinopathy. While seipin loss of function leads to severe congenital lipodystrophy, the effects of seipin N-glycosylation mutations on lipid balance in the nervous system are unknown. In this study, we show that expression of seipin N-glycosylation mutant N88S led to decreased triglyceride content in astrocytoma and motor neuron cell lines. This was corrected by supplementation with exogenous oleic acid. Upon oleic acid loading, seipin N88S protein was relocated from the endoplasmic reticulum (ER) to the surface of lipid droplets and this was paralleled by alleviation of ER stress induced by the mutant protein. This effect was not limited to seipin N88S, as oleic acid loading also reduced tunicamycin induced ER stress in motor neuron cells. Furthermore, both seipin N88S and tunicamycin induced ER stress were decreased by inhibiting lipolysis, suggesting that lipid droplets protected neuronal cells from ER stress. In developing zebrafish larvae, seipin N88S expression led to triglyceride imbalance and reduced spontaneous free swimming. Importantly, supplementation with exogenous oleic acid reduced ER stress in the zebrafish head and increased fish motility. We propose that decreased triglyceride content contributes to the pathology induced by seipin N88S, and that rescuing triglyceride levels may provide a novel therapeutic strategy in seipinopathy.