The ER-Associated Degradation Adaptor Protein Sel1L Regulates LPL Secretion and Lipid Metabolism

H. Sha, S. Sun, A. Francisco, N. Ehrhardt, Z.Q. Xue, L. Liu, F.B.J. Mattijssen, A.H. Kersten

Research output: Contribution to journalArticleAcademicpeer-review

50 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)458-470
JournalCell Metabolism
Volume20
Issue number3
DOIs
Publication statusPublished - 2014

Keywords

  • reticulum-associated-degradation
  • endoplasmic-reticulum
  • lipoprotein-lipase
  • caenorhabditis-elegans
  • membrane-protein
  • stress
  • deficiency
  • maturation
  • disease
  • liver

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