The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology

Department of Pharmacology, University of Texas Southwestern Medical School, Dallas, TX 75390, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2008; 104(52):20890-5. DOI: 10.1073/pnas.0704154104
Source: PubMed


Lipodystrophy is a disorder characterized by a loss of adipose tissue often accompanied by severe hypertriglyceridemia, insulin resistance, diabetes, and fatty liver. It can be inherited or acquired. The most severe inherited form is Berardinelli-Seip Congenital Lipodystrophy Type 2, associated with mutations in the BSCL2 gene. BSCL2 encodes seipin, the function of which has been entirely unknown. We now report the identification of yeast BSCL2/seipin through a screen to detect genes important for lipid droplet morphology. The absence of yeast seipin results in irregular lipid droplets often clustered alongside proliferated endoplasmic reticulum (ER); giant lipid droplets are also seen. Many small irregular lipid droplets are also apparent in fibroblasts from a BSCL2 patient. Human seipin can functionally replace yeast seipin, but a missense mutation in human seipin that causes lipodystrophy, or corresponding mutations in the yeast gene, render them unable to complement. Yeast seipin is localized in the ER, where it forms puncta. Almost all lipid droplets appear to be on the ER, and seipin is found at these junctions. Therefore, we hypothesize that seipin is important for droplet maintenance and perhaps assembly. In addition to detecting seipin, the screen identified 58 other genes whose deletions cause aberrant lipid droplets, including 2 genes encoding proteins known to activate lipin, a lipodystrophy locus in mice, and 16 other genes that are involved in endosomal-lysosomal trafficking. The genes identified in our screen should be of value in understanding the pathway of lipid droplet biogenesis and maintenance and the cause of some lipodystrophies.

Download full-text


Available from: Joel M Goodman, Feb 24, 2014
  • Source
    • " , 2009 ; Dugail , 2014 ) . Lipid - exchange is likely to be the functional linkage between LDs and ER , peroxisomes and mitochondria . The association between the ER and LDs seems to occur even after budding of the LDs , with permanent contacts between these organelles being reported in different cells types ( Blanchette - Mackie et al . , 1995 ; Szymanski et al . , 2007 ) . Peroxisomes and mitochondria are frequently found in close association with LDs ( Novikoff et al . , 1980 ; Schrader , 2001 ; Binns et al . , 2006 ; Sturmey et al . , 2006 ; Shaw et al . , 2008 ) . Those contacts may link fatty acid supply by lipolysis in LDs with peroxisomal and mitochondrial fatty acid β - oxidation ."
    [Show abstract] [Hide abstract]
    ABSTRACT: Membrane-bound organelles such as mitochondria, peroxisomes, or the endoplasmic reticulum (ER) create distinct environments to promote specific cellular tasks such as ATP production, lipid breakdown, or protein export. During recent years, it has become evident that organelles are integrated into cellular networks regulating metabolism, intracellular signaling, cellular maintenance, cell fate decision, and pathogen defence. In order to facilitate such signaling events, specialized membrane regions between apposing organelles bear distinct sets of proteins to enable tethering and exchange of metabolites and signaling molecules. Such membrane associations between the mitochondria and a specialized site of the ER, the mitochondria associated-membrane (MAM), as well as between the ER and the plasma membrane (PAM) have been partially characterized at the molecular level. However, historical and recent observations imply that other organelles like peroxisomes, lysosomes, and lipid droplets might also be involved in the formation of such apposing membrane contact sites. Alternatively, reports on so-called mitochondria derived-vesicles (MDV) suggest alternative mechanisms of organelle interaction. Moreover, maintenance of cellular homeostasis requires the precise removal of aged organelles by autophagy-a process which involves the detection of ubiquitinated organelle proteins by the autophagosome membrane, representing another site of membrane associated-signaling. This review will summarize the available data on the existence and composition of organelle contact sites and the molecular specializations each site uses in order to provide a timely overview on the potential functions of organelle interaction.
    Full-text · Article · Sep 2015 · Frontiers in Cell and Developmental Biology
  • Source
    • "It has been shown that human wt seipin forms oligomers of 12 subunits (Sim et al., 2013). At least for the yeast seipin homolog FLD1, these oligomers are involved in the generation of lipid droplets at the ER-LD junctions (Szymanski et al., 2007). We reasoned that mutated seipin might fail to assemble correctly. "

    Full-text · Dataset · Sep 2015
  • Source
    • " , in seed tissues , where TAG accumulation rates are substantial , alterations in SEIPIN1 expression exhibited visible , lipid - related phenotypes that impacted overall seed oil yields . DISCUSSION SEIPIN homologs in yeast and animal systems are believed to play an important role in lipid storage , especially in regulating the formation of LDs ( Szymanski et al . , 2007 ; Fei et al . , 2011a ) . Indeed , genetic mutations in the human SEIPIN gene lead to congenital lipodystrophy and inefficient compartmentalization of storage lipids ; similarly , the deletion of SEIPIN in yeast cells leads to aberrant packaging of neutral lipids ( Cartwright and Goodman , 2012 ) . However , there is essentially no info"
    [Show abstract] [Hide abstract]
    ABSTRACT: The lipodystrophy protein SEIPIN is important for lipid droplet (LD) biogenesis in human and yeast cells. In contrast with the single SEIPIN genes in humans and yeast, there are three SEIPIN homologs in Arabidopsis thaliana, designated SEIPIN1, SEIPIN2, and SEIPIN3. Essentially nothing is known about the functions of SEIPIN homologs in plants. Here, a yeast (Saccharomyces cerevisiae) SEIPIN deletion mutant strain and a plant (Nicotiana benthamiana) transient expression system were used to test the ability of Arabidopsis SEIPINs to influence LD morphology. In both species, expression of SEIPIN1 promoted accumulation of large-sized lipid droplets, while expression of SEIPIN2 and especially SEIPIN3 promoted small LDs. Arabidopsis SEIPINs increased triacylglycerol levels and altered composition. In tobacco, endoplasmic reticulum (ER)-localized SEIPINs reorganized the normal, reticulated ER structure into discrete ER domains that colocalized with LDs. N-terminal deletions and swapping experiments of SEIPIN1 and 3 revealed that this region of SEIPIN determines LD size. Ectopic overexpression of SEIPIN1 in Arabidopsis resulted in increased numbers of large LDs in leaves, as well as in seeds, and increased seed oil content by up to 10% over wild-type seeds. By contrast, RNAi suppression of SEIPIN1 resulted in smaller seeds and, as a consequence, a reduction in the amount of oil per seed compared with the wild type. Overall, our results indicate that Arabidopsis SEIPINs are part of a conserved LD biogenesis machinery in eukaryotes and that in plants these proteins may have evolved specialized roles in the storage of neutral lipids by differentially modulating the number and sizes of lipid droplets.
    Full-text · Article · Sep 2015 · The Plant Cell
Show more