Journal
CELL METABOLISM
Volume 20, Issue 3, Pages 458-470Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2014.06.015
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Funding
- Netherlands Organization for Health Research and Development ZonMW [40-00812-98-08030]
- NIH [P01HL090553, P01HL028481, R01DK082582]
- NCATS [UL1TR000124]
- Cedars-Sinai Medical Center
- Chinese National Science Foundation [31371391]
- American Diabetes Association (ADA) [07-08-JF-47, 1-12-CD-04]
- Center for Vertebrate Genomics at Cornell University
- ADA
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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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