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

Abstract

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 endosomallysosomal 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. BSCL2 ͉ lipid bodies

ER Membrane Phospholipids and Surface Tension Control Cellular Lipid Droplet Formation

“…These conditions correspond, for example, to the accumulation of negatively curved lipids such as diacylglycerols, PA, or cholesterol ( Figure 1G tensions ( Figure 4G). Our prediction is consistent with reported regulations of GPAT4 trafficking from ER to LDs: in increased PA levels in the ER membrane of various cell types lacking Seipin protein, a massive transfer of GPAT4 from the ER to almost all LDs is observed in comparison with normal cells (Fei et al, 2011;Pagac et al, 2016;Szymanski et al, 2007;Wang et al, 2016); likewise, under conditions where GPAT4 should exclusively remain in the ER membrane of fly cells (Wilfling et al, 2014b), the induction of cholesterol accumulation in the membrane restored GPAT4 targeting from ER to LDs (Wilfling et al, 2014b). Consequently, ER tension and phospholipid composition seem to be critical for determining the protein composition of LD during formation.…”

“…Currently a group of proteins, including for example Seipin or the fat storage-inducing transmembrane proteins, has been identified as important for LD formation (Cartwright et al, 2015;Choudhary et al, 2015;Pol et al, 2014;Szymanski et al, 2007;Wang et al, 2016). These proteins probably regulate different steps in LD formation up to LD budding, but their exact functions are still unclear.…”

A Patient with Congenital Generalized Lipodystrophy Due To a Novel Mutation in BSCL2: Indications for Secondary Mitochondrial Dysfunction

“…Consistent with the preservation of transmembrane domain 1, which has been shown to be critical for ER retention (Ito et al 2008), both aberrant proteins localized to the ER like wild-type protein. While its exact function remains to be established, recent studies in yeast and human cells have shown that lack of seipin results in altered lipid droplet morphology and number, strongly implicating this protein in lipid storage (Szymanski et al 2007;Fei et al 2008;Boutet et al 2009). In addition, seipin plays a role in lipid biosynthesis, as lymphoblastoid cells from CGL2 patients displayed a defect in D9-desaturase (stearoyl-CoA desaturase; SCD) activity (Boutet et al 2009).…”

Disruption of theArabidopsisCGI-58 homologue produces Chanarin–Dorfman-like lipid droplet accumulation in plants

“…It is becoming increasingly apparent that the lipid droplets in cells play active roles in cellular processes, and are not just deposits for carbon storage (29). Evidence points to an interaction of lipid droplets with other subcellular compartments (30)(31)(32)(33)(34) and the appearance and disappearance of lipid droplets in cells may generally be used as a transient compartment for membrane trafficking or as metabolic reservoirs for membrane acyl groups (35,36). Still others have suggested a possible role for lipid droplets in signal transduction (37).…”