Seipin: a mysterious protein.

Division of Nutrition and Metabolic Diseases, the Department of Internal Medicine and the Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Trends in Molecular Medicine (Impact Factor: 10.11). 10/2004; 10(9):440-4. DOI: 10.1016/j.molmed.2004.07.009
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    ABSTRACT: Infectious hepatitis C virus (HCV) particle assembly starts at the surface of lipid droplets, cytoplasmic organelles responsible for neutral fat storage. We analyzed the relationship between HCV and seipin, a protein involved in lipid droplet maturation. Although seipin overexpression did not affect the total mean volume occupied by lipid droplets nor the total triglyceride and cholesterol ester levels per cell, it caused an increase in the mean diameter of lipid droplets by 60%, while decreasing their total number per cell. The latter two effects combined resulted in a 34% reduction of the total outer surface area of lipid droplets per cell, with a proportional decrease in infectious viral particle production, probably due to a defect in particle assembly. These results suggest that the available outer surface of lipid droplets is a critical factor for HCV release, independent of the neutral lipid content of the cell.
    Journal of General Virology 08/2013; DOI:10.1099/vir.0.054593-0 · 3.53 Impact Factor
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    ABSTRACT: Seipin gene was originally found to be responsible for type 2 congenital lipodystrophy and involved in lipid droplet formation. Seipin is highly expressed in the central nervous system as well. Seipin mutations have been identified in motor neuron diseases such as Silver syndrome and spastic paraplegia. In this study, we generated neuron-specific seipin knockout mice (seipin-nKO) to investigate the influence of seipin deficiency on locomotion and affective behaviors. In comparison with control mice, 8-week-old male seipin-nKO mice, but not female mice, displayed anxiety- and depression-like behaviors as assessed by open-field, elevated plus-maze, forced swim and tail suspension tests. However, neither male nor female seipin-nKO mice showed locomotion deficits in swimming tank and rotarod tests. Interestingly, the mRNA and protein levels of peroxisome proliferator-activated receptor gamma (PPARγ) in the hippocampus and cortex were lower in male seipin-nKO mice, but not female mice, than controls. In seipin-nKO mice, plasma levels of sex hormones including 17β-estradiol (E2) in females and testosterone in males as well as corticosterone were not altered compared to controls. The treatment of male seipin-nKO mice with E2 ameliorated the anxiety- and depression-like behaviors and remarkably increased PPARγ levels. The PPARγ agonist rosiglitazone alleviated affective disorders in male seipin-nKO mice. Notably, anxiety- and depression-like behaviors appeared in female seipin-nKO mice after ovariectomy, which was associated with low PPARγ expression. Collectively, these results indicate that neuronal seipin deficiency causing reduced PPARγ levels leads to affective disorders in male mice that are rescued by E2-increased PPARγ expression.
    Human Molecular Genetics 03/2014; DOI:10.1093/hmg/ddu126 · 6.68 Impact Factor
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    ABSTRACT: Gain-of-toxic-function mutations in Seipin (Asparagine 88 to Serine (N88S) and Serine 90 to Leucine (S90L) mutations, both of which disrupt the N-glycosylation) cause autosomal dominant motor neuron diseases. However, the mechanism of how these missense mutations lead to motor neuropathy is unclear. Here, we analyze the impact of disruption of N-glycosylation of Seipin on synaptic transmission by overexpressing mutant Seipin in cultured cortical neurons via lentiviral infection. Immunostaining shows that overexpressed Seipin is partly co-localized with synaptic vesicle marker synaptophysin. Electrophysiological recordings reveal that the Seipin mutation significantly decreases the frequency but not the amplitudes of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs). The amplitude of both evoked EPSC and IPSC are also compromised by mutant Seipin overexpression. The readily releasable pool and vesicular release probability of synaptic vesicles are both altered in neurons overexpressing Seipin-N88S, while neither γ-amino butyric acid (GABA) nor α-Amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) induced whole cell currents are affected. Moreover, electron microscopy analysis reveals decreased number of morphologically docked synaptic vesicles in Seipin-N88S-expressing neurons. These data demonstrate that Seipin-N88S mutation impairs synaptic neurotransmission, possibly by regulating the priming and docking of synaptic vesicles at the synapse. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 12/2013; DOI:10.1111/jnc.12638 · 4.24 Impact Factor