The ER-Associated Degradation Adapter Protein Sel1L Regulates Triglyceride Metabolism via Lipoprotein Lipase

  • Haibo Sha (Creator)
  • Adams Francisco (Creator)
  • Shengyi Sun (Creator)
  • Nicole Ehrhardt (Creator)
  • Zhen Xue (Creator)
  • Lei Liu (Creator)
  • Peter Lawrence (Creator)
  • Frits Mattijssen (Creator)
  • Robert Gruber (Creator)
  • Muhammad S. Panhwar (Creator)
  • J.T. Brenna (Creator)
  • Hang Shi (Creator)
  • Bingzhong Xue (Creator)
  • Sander Kersten (Creator)
  • André Bensadoun (Creator)
  • Miklòs Péterfy (Creator)
  • Qiaoming Long (Creator)
  • Ling Qi (Creator)

Dataset

Description

Sel1L is an adaptor protein for the E3 ligase Hrd1 in the endoplasmic reticulum-associated degradation (ERAD), but its physiological role in a cell-type-specific manner remains unclear. Here we show that mice with adipocyte-specific Sel1L deficiency are resistant to diet-induced obesity and exhibit postprandial hypertriglyceridemia. Mechanistically, our data demonstrate a critical requirement of Sel1L for the secretion of lipoprotein lipase (LPL), independently of its role in Hrd1-mediated ERAD and ER homeostasis. Further biochemical analyses revealed that Sel1L physically interacts and stabilizes the LPL maturation complex consisted of LPL and lipase-maturation factor 1 (LMF1). In the absence of Sel1L, LPL is retained in the ER and prone to the formation of protein aggregates, which are degraded by autophagy-mediated degradation. The Sel1L-mediated control of LPL secretion is seen in other LPL-expressing cell types as well such as cardiac muscle and macrophages. Thus, our study reports a novel role of Sel1L in LPL secretion and systemic lipid metabolism.
Date made available18 May 2015
PublisherWageningen University

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