Seipin oligomers can interact directly with AGPAT2 and lipin 1, physically scaffolding critical regulators of adipogenesis

This work was supported by a Merit Scholarship from the Islamic Development Bank (to M.M.U.T.), The Agency for Science, Technology and Research, Singapore (A*STAR) (M.F.M.S), the Medical Research Council (MRC) [NIRG GO800203 and Research Grant MR/L002620/1 (to J.J.R.), Program GrantG09000554 (to S.O.R)], The Wellcome Trust [078986/Z/06/Z (to S.O.R.)], the MRC Centre for Obesity and Related Metabolic Disorders (MRC-CORD) [GO600717] and the NIHR Comprehensive Biomedical Research Centre [CG50826].Peer reviewedPublisher PD

Analysis of naturally occurring mutations in the human lipodystrophy protein seipin reveals multiple potential pathogenic mechanisms

Peer reviewedPublisher PD

Amyotrophic lateral sclerosis (ALS)-associated VAPB-P56S inclusions represent an ER quality control compartment

BACKGROUND: Protein aggregation and the formation of intracellular inclusions are a central feature of many neurodegenerative disorders, but precise knowledge about their pathogenic role is lacking in most instances. Here we have characterized inclusions formed in transgenic mice carrying the P56S mutant form of VAPB that causes various motor neuron syndromes including ALS8.RESULTS: Inclusions in motor neurons of VAPB-P56S transgenic mice are characterized by the presence of smooth ER-like tubular profiles, and are immunoreactive for factors that operate in the ER associated degradation (ERAD) pathway, including p97/VCP, Derlin-1, and the ER membrane chaperone BAP31. The presence of these inclusions does not correlate with signs of axonal and neuronal degeneration, and axotomy leads to their gradual disappearance, indicating that they represent reversible structures. Inhibition of the proteasome and knockdown of the ER membrane chaperone BAP31 increased the size of mutant VAPB inclusions in primary neuron cultures, while knockdown of TEB4, an ERAD ubiquitin-protein ligase, reduced their size. Mutant VAPB did not codistribute with mutant forms of seipin that are associated with an autosomal dominant motor neuron disease, and accumulate in a protective ER derived compartment termed ERPO (ER protective organelle) in neurons.CONCLUSIONS: The data indicate that the VAPB-P56S inclusions represent a novel reversible ER quality control compartment that is formed when the amount of mutant VAPB exceeds the capacity of the ERAD pathway and that isolates misfolded and aggregated VAPB from the rest of the ER. The presence of this quality control compartment reveals an additional level of flexibility of neurons to cope with misfolded protein stress in the ER

Berardinelli-Seip Syndrome

We have reported two cases of Berardinelli-syndrome in a family which is a rare autosomal recessive disorder of the adipose tissue, originally described by Berardinelli and Seip, has been reported in approximately 120 patients of various ethnic origins. Assuming that only 1 in 4 patients is reported.Patients present with acanthosis nigricans (dark velvety pigmentation of the skin) in the axilla, neck or groin, severe insulin resistance, high levels of serum insulin and serum triglycerides.The other clinical features consist of enlarged hands, feet and prominent mandible (acromegaloid features), increased sweating, umbilical hernia and lytic lesions (bone appear to be eaten-up on X-rays) in long bones of the upper and lower extremities (arms, forearm, hands, thigh, calf, legs and feet) such as humerus, femur, etc. Hepatomegaly from fatty liver is almost universal and may ultimately lead to cirrhosis. Splenomegaly is common. Nearly all patients have a prominent umbilicus or frank umbilical hernia. Females present with enlarged clitoris, increased body hair, absence of or irregular menstrual cycles, and polycystic ovaries (enlarged ovaries). Only a few affected women have had successful pregnancies, whereas affected men have normal fertilit

Biogenesis of the multifunctional lipid droplet: lipids, proteins, and sites

Lipid droplets (LDs) are ubiquitous dynamic organelles that store and supply lipids in all eukaryotic and some prokaryotic cells for energy metabolism, membrane synthesis, and production of essential lipid-derived molecules. Interest in the organelle's cell biology has exponentially increased over the last decade due to the link between LDs and prevalent human diseases and the discovery of new and unexpected functions of LDs. As a result, there has been significant recent progress toward understanding where and how LDs are formed, and the specific lipid pathways that coordinate LD biogenesis

Inverse correlation between VEGF and soluble VEGF receptor 2 in POEMS with AIDP responsive to intravenous immunoglobulin

POEMS (polyneuropathy, organomegaly, endocrinopathy, M-band, and skin changes) syndrome is characterized by chronic progressive polyneuropathy and plasma-cell dyscrasia. A major diagnostic criterion of POEMS is elevation of circulating vascular endothelial growth factor (VEGF), which is believed to play a pathogenic role in this disease. We report a case of POEMS that presented as relapsing acute inflammatory demyelinating polyneuropathy, in which complete remission after intravenous immunoglobulin (IVIg) treatment was unexpectedly observed. At clinical nadir, the VEGF level was 30-fold higher, and the soluble form of VEGF receptor 2 (sVEGFR2), which acts as a decoy for VEGF, was 2.7-fold lower than normal. These changes combined might contribute to the pathogenesis of POEMS, inducing vascular permeability and tissue edema. At 9-month follow-up, during clinical remission, VEGF and sVEGFR2 were near normal values. sVEGFR2 reduction is a new finding in POEMS. IVIg treatment may benefit POEMS patients with acute neuropathy by downgrading VEGF release induced by inflammatory cytokines

Fat storage-inducing transmembrane (FIT or FITM) proteins are related to lipid phosphatase/phosphotransferase enzymes

Fat storage-inducing transmembrane (FIT or FITM) proteins have been implicated in the partitioning of triacylglycerol to lipid droplets and the budding of lipid droplets from the ER. At the molecular level, the sole relevant interaction is that FITMs directly bind to triacyglycerol and diacylglycerol, but how they function at the molecular level is not known.Saccharomyces cerevisiaehas two FITM homologues: Scs3p and Yft2p. Scs3p was initially identified because deletion leads to inositol auxotrophy, with an unusual sensitivity to addition of choline. This strongly suggests a role for Scs3p in phospholipid biosynthesis. Looking at the FITM family as widely as possible, we found that FITMs are widespread throughout eukaryotes, indicating presence in the last eukaryotic common ancestor. Protein alignments also showed that FITM sequences contain the active site of lipid phosphatase/phosphotransferase (LPT) enzymes. This large family transfers phosphate-containing headgroups either between lipids or in exchange for water. We confirmed the prediction that FITMs are related to LPTs by showing that single amino-acid substitutions in the presumptive catalytic site prevented their ability to rescue growth of the mutants on low inositol/high choline media when over-expressed. The substitutions also prevented rescue of other phenotypes associated with loss of FITM in yeast, including mistargeting of Opi1p, defective ER morphology, and aberrant lipid droplet budding. These results suggest that Scs3p, Yft2p and FITMs in general are LPT enzymes involved in an as yet unknown critical step in phospholipid metabolism