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The ER-associated degradation adaptor protein Sel1L regulates LPL secretion and lipid metabolism.

Cell Metab.2014 Sep 02;20(3):458-70. Epub 2014 Jul 24
Haibo Sha 1 , Shengyi Sun 2 , Adam B Francisco 3 , Nicole Ehrhardt 4 , Zhen Xue 1 , Lei Liu 1 , Peter Lawrence 1 , Frits Mattijssen 5 , Robert D Guber 1 , Muhammad S Panhwar 6 , J Thomas Brenna 1 , Hang Shi 7 , Bingzhong Xue 7 , Sander Kersten 8 , André Bensadoun 1 , Miklós Péterfy 9 , Qiaoming Long 10 , Ling Qi 11
Haibo Sha 1 , Shengyi Sun 2 , Adam B Francisco 3 , Nicole Ehrhardt 4 , Zhen Xue 1 , Lei Liu 1 , Peter Lawrence 1 , Frits Mattijssen 5 , Robert D Guber 1 , Muhammad S Panhwar 6 , J Thomas Brenna 1 , Hang Shi 7 , Bingzhong Xue 7 , Sander Kersten 8 , André Bensadoun 1 , Miklós Péterfy 9 , Qiaoming Long 10 , Ling Qi 11
+ et al

[No authors listed]

Author information
  • 1 Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
  • 2 Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA.
  • 3 Department of Animal Science, Cornell University, Ithaca, NY 14853, USA.
  • 4 Department of Biomedical Sciences, Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 5 Nutrition Metabolism and Genomics Group, Wageningen University, Wageningen 6703HD, the Netherlands.
  • 6 Weill Cornell Medical College in Qatar, P.O. Box 24144, Education City, Doha, Qatar.
  • 7 Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
  • 8 Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Nutrition Metabolism and Genomics Group, Wageningen University, Wageningen 6703HD, the Netherlands.
  • 9 Department of Biomedical Sciences, Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
  • 10 Laboratory Animal Research Center, Medical College of Soochow University, Suzhou, Jiangsu 215006, China.
  • 11 Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA. Electronic address: lq35@cornell.edu.

摘要

Sel1L is an essential adaptor protein for the E3 ligase Hrd1 in the endoplasmic reticulum (ER)-associated degradation (ERAD), a universal quality-control system in the cell; but its physiological role remains unclear. Here we show that mice with adipocyte-specific Sel1L deficiency are resistant to diet-induced obesity and exhibit postprandial hypertriglyceridemia. Further analyses reveal that Sel1L is indispensable for the secretion of lipoprotein lipase (LPL), independent of its role in Hrd1-mediated ERAD and ER homeostasis. Sel1L physically interacts with and stabilizes the LPL maturation complex consisting of LPL and lipase maturation factor 1 (LMF1). In the absence of Sel1L, LPL is retained in the ER and forms protein aggregates, which are degraded primarily by autophagy. The Sel1L-mediated control of LPL secretion is also seen in other LPL-expressing cell types including cardiac myocytes and macrophages. Thus, our study reports a role of Sel1L in LPL secretion and systemic lipid metabolism.

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