Seipin: from human disease to molecular mechanism

Cartwright, Bethany R.; Goodman, Joel M.

doi:10.1194/jlr.r023754

Cited by 111 publications

(96 citation statements)

References 78 publications

(143 reference statements)

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“…We found that the wild-type and neuronal seipinopathy mutation, S90L, expressed in fld1D gave normal LDs (Fig. 8B), consistent with previous observations (Cartwright and Goodman, 2012;Fei et al, 2008b;Szymanski et al, 2007). Another neuronal seipinopathy mutation, N88S, gave normal LDs previously (Fei et al, 2008b) but larger LDs in our analyses, which might reflect a difference in expression level or quantification.…”

Section: Fld1 Is Required For Ldb16 Stabilitysupporting

confidence: 92%

“…The seipin recessive mutations in humans are associated with the most severe form of lipodystrophy CGL2, whereas its dominant mutations cause neuronal seipinopathies (Cartwright and Goodman, 2012). Seipin/Fld1 localizes to ER and is enriched at the ER-LD contact sites (Fei et al, 2011a;Szymanski et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…How seipin/Fld1 controls LD size remains obscure (Cartwright and Goodman, 2012). Because LDs in fld1D appear more fusogenic, deficiency of Fld1 might cause LD enlargement via LD fusion (Fei et al, 2008b).…”

Section: Introductionmentioning

confidence: 99%

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Size control of lipid droplets in budding yeast requires a collaboration of Fld1 and Ldb16

Wang

Miao

Chang

2014

Journal of Cell Science

112

155

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The human congenital generalized lipodystrophy type 2 protein seipin (Fld1 in budding yeast) controls lipid droplet (LD) size through an unknown mechanism. Here, we report that deletion of yeast LDB16/YCL005W, similar to deletion of FLD1, causes supersized and small clustered LDs, altered phospholipid metabolism and impaired distribution of a subset of LD proteins. Ldb16 is a transmembrane protein in the endoplasmic reticulum (ER) that assembles together with Fld1 at ER-LD contact sites, a region that probably links neutral lipid synthesis with LD assembly. The formation of the Fld1-Ldb16 complex involves putative transmembrane segments of both proteins, thus, directly contributing to the maintenance of LD morphology. The stability of Ldb16 requires Fld1, as Ldb16 is subjected to ER-associated degradation (ERAD) in the absence of Fld1 but is stabilized when Fld1 is present. Strikingly, human seipin, but not yeast Fld1, complements the defects in LDs in ldb16D yeast, implying that seipin can substitute for the function of the Fld1-Ldb16 complex. We propose that human seipin might adopt the architecture of the yeast Fld1-Ldb16 complex in order to properly maintain the size of LDs.

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Section: Fld1 Is Required For Ldb16 Stabilitysupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Size control of lipid droplets in budding yeast requires a collaboration of Fld1 and Ldb16

Wang

Miao

Chang

2014

Journal of Cell Science

112

155

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“…Some studies indicate that seipin is involved in adipogenesis, lipid metabolism and lipid droplet (LD) biogenesis and maintenance [7][8][9][10][11][12]. Notably, knocking down seipin with short hairpin RNA alters terminal adipocyte differentiation in C3H10T1/2 mesenchymal stem cells [13] or 3 T3-L1 adipocyte cell lines, with a downregulation of transcription factors involved in adipogenesis and of their downstream lipogenic target genes [13,14].…”

Section: Introductionmentioning

confidence: 99%

Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice

Prieur¹,

Dollet²,

Takahashi³

et al. 2013

Diabetologia

131

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Aims/hypothesis Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype. Methods Bscl2−/− mice were generated and phenotyped. X. Prieur, L. Dollet and M. Takahashi contributed equally to this study.Electronic supplementary material The online version of this article

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“…A common fi nding to many of these screens was the identifi cation of the seipins, BSCL2 in mammals and FLD1 in yeast (reviewed in Ref. 70 ). Loss-offunction mutations in seipin account for a severe form of congenital lipodystrophy (Berardinelli-Seip congenital lipodystrophy) and striking changes in lipid droplet size, number, and distribution.…”

Section: The Cld Proteomementioning

confidence: 99%

Lipid droplet formation on opposing sides of the endoplasmic reticulum

Sturley

Hussain

2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org consumes signifi cant chemical energy and is therefore tightly regulated and coordinated with frugal transport processes to assimilate them from the environment and/or store them safely. Lipids enter the cytoplasm as acids (free fatty acids) or alcohols (e.g., free cholesterol). High concentrations of free fatty acids and sterols are injurious to cells, whereas alcohols such as diacylglycerol are bioactive at low concentrations as signaling molecules. Consequently, effi cient systems have evolved to limit their concentrations but retain their availability by coesterifi cation of the acids and alcohols into neutral lipids.Neutral lipids confer several selective advantages to the cell and organism in which they reside. They provide a conduit for detoxifi cation of free fatty acids and a key reservoir of membrane components and energy. Esterifi cation of sterols with FA to form steryl esters (SE) [e.g., cholesteryl ester (CE)] provides for future membrane rebuilding and remodeling. Triacylglycerol (TG), a fatty acyl ester derivative of glycerol, represents the major energy depot of all eukaryotic and some bacterial cells. The energy of complete oxidation of the alkyl chains of TG (38 KJ/g) is more than twice the same weight of carbohydrate or protein, and unlike polysaccharide, TG carries no extra weight as water of solvation. Similarly, esterifi ed long-and shortchain alcohols, such as wax esters and diesters, form an important water repellant permeability barrier in the skin and fur of mammals and the cuticle of plants.The majority of neutral lipid synthesis is completed at the endoplasmic reticulum (ER). However, neutral lipid synthesis poses two problems: neutral lipids have limited solubility in the ER membrane bilayer, and they are immiscible Lipids are critical determinants of membrane integrity, important sources of energy, and in some cells, substrates for the synthesis of hormones. Endogenous lipid synthesis

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Seipin: from human disease to molecular mechanism

Cited by 111 publications

References 78 publications

Size control of lipid droplets in budding yeast requires a collaboration of Fld1 and Ldb16

Size control of lipid droplets in budding yeast requires a collaboration of Fld1 and Ldb16

Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice

Lipid droplet formation on opposing sides of the endoplasmic reticulum

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