Molecular characterization of seipin and its mutants: implications for seipin in triacylglycerol synthesis

Fei, Weihua; Li, Hui; Shui, Guanghou; Kapterian, Tamar S.; Bielby, Christopher; Du, Ximing; Brown, Andrew; Li, Peng; Wenk, Markus R.; Liu, Pingsheng; Yang, Hongyuan

doi:10.1194/jlr.m017566

Cited by 81 publications

(89 citation statements)

References 30 publications

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“…We have previously shown that within cells the lipins form tetramers (34), and by atomic force microscopy, we have found that recombinant lipin 1 can form even higher order structures on lipin bilayers (35). In addition, lipin 1 has been found to interact with the human lipodystrophy protein seipin (36), and seipin itself has been found to form large oligomeric structures (37)(38)(39). Although the identification of lipin localization to punctate spots is interesting, further study will be necessary to uncover the nature and/or function of lipin protein cellular localization to these structures.…”

Section: Discussionmentioning

confidence: 99%

Lipin 2 Binds Phosphatidic Acid by the Electrostatic Hydrogen Bond Switch Mechanism Independent of Phosphorylation

Eaton

Takkellapati

Lawrence

et al. 2014

Journal of Biological Chemistry

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Background: Lipin 2 is a phosphatidic acid phosphatase (PAP) responsible for DAG formation at the ER membrane during lipogenesis. Results: A combination of biochemical approaches is used to characterize lipin 2 phosphatase activity and regulation. Conclusion: The electrostatic charge of PA regulates activity, but phosphorylation does not.Significance: These findings demonstrate differential regulation of PAP activity within the lipin family.

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Section: Discussionmentioning

confidence: 99%

Lipin 2 Binds Phosphatidic Acid by the Electrostatic Hydrogen Bond Switch Mechanism Independent of Phosphorylation

Eaton

Takkellapati

Lawrence

et al. 2014

Journal of Biological Chemistry

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“…The hypertrophy of adipocytes is likely associated with the role of SEIPIN in LD expansion. Although aggregates of small LDs were found in SEIPIN/Fld1-deficient cells (9)(10)(11)27), the most striking change was the formation of giant/supersized LDs (8,10,12). Upregulation of PA, a fusogenic lipid, is believed to contribute to the formation of supersized LDs (21,28), and indeed, PA is increased in ASKO adipose tissue ( Fig.…”

Section: Seipin Adipocyte Hypertrophy and Progressive Lipodystrophymentioning

confidence: 99%

Adipose-Specific Knockout of Seipin/Bscl2 Results in Progressive Lipodystrophy

et al. 2014

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Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is the most severe form of human lipodystrophy, characterized by an almost complete loss of adipose tissue and severe insulin resistance. BSCL2 is caused by loss-of-function mutations in the BSCL2/SEIPIN gene, which is upregulated during adipogenesis and abundantly expressed in the adipose tissue. The physiological function of SEIPIN in mature adipocytes, however, remains to be elucidated. Here, we generated adipose-specific Seipin knockout (ASKO) mice, which exhibit adipocyte hypertrophy with enlarged lipid droplets, reduced lipolysis, adipose tissue inflammation, progressive loss of white and brown adipose tissue, insulin resistance, and hepatic steatosis. Lipidomic and microarray analyses revealed accumulation/imbalance of lipid species, including ceramides, in ASKO adipose tissue as well as increased endoplasmic reticulum stress. Interestingly, the ASKO mice almost completely phenocopy the fat-specific peroxisome proliferator–activated receptor-γ (Pparγ) knockout (FKO-γ) mice. Rosiglitazone treatment significantly improved a number of metabolic parameters of the ASKO mice, including insulin sensitivity. Our results therefore demonstrate a critical role of SEIPIN in maintaining lipid homeostasis and function of adipocytes and reveal an intimate relationship between SEIPIN and PPAR-γ.

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“…While physiological binding partners of seipin have yet to be identifi ed, it is clear that seipin can self-associate ( 51,59 ). When extracted from yeast membranes with Triton X-100, seipin behaves as a discrete and stable oligomer.…”

Section: Domains Topology and Oligomerizationmentioning

confidence: 99%