title: The ER-associated degradation adaptor protein Sel1L regulates LPL secretion and lipid metabolism.
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.
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: Haibo
authors: H
authors: Sha
authors: Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA.
authors: Shengyi
authors: S
authors: Sun
authors: Department of Animal Science, Cornell University, Ithaca, NY 14853, USA.
authors: Adam B
authors: AB
authors: Francisco
authors: Department of Biomedical Sciences, Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Nicole
authors: N
authors: Ehrhardt
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: Zhen
authors: Z
authors: Xue
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: Lei
authors: L
authors: Liu
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: Peter
authors: P
authors: Lawrence
authors: Nutrition Metabolism and Genomics Group, Wageningen University, Wageningen 6703HD, the Netherlands.
authors: Frits
authors: F
authors: Mattijssen
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: Robert D
authors: RD
authors: Guber
authors: Weill Cornell Medical College in Qatar, P.O. Box 24144, Education City, Doha, Qatar.
authors: Muhammad S
authors: MS
authors: Panhwar
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: J Thomas
authors: JT
authors: Brenna
authors: Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
authors: Hang
authors: H
authors: Shi
authors: Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
authors: Bingzhong
authors: B
authors: Xue
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Nutrition Metabolism and Genomics Group, Wageningen University, Wageningen 6703HD, the Netherlands.
authors: Sander
authors: S
authors: Kersten
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: André
authors: A
authors: Bensadoun
authors: 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.
authors: Miklós
authors: M
authors: Péterfy
authors: Laboratory Animal Research Center, Medical College of Soochow University, Suzhou, Jiangsu 215006, China.
authors: Qiaoming
authors: Q
authors: Long
authors: 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.
authors: Ling
authors: L
authors: Qi
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D060746:Endoplasmic Reticulum-Associated Degradation; D005260:Female; D017353:Gene Deletion; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008071:Lipoprotein Lipase / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D066329:Protein Aggregates; D055503:Protein Multimerization; D011506:Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C546367:LMF1 protein, mouse; D008565:Membrane Proteins; D066329:Protein Aggregates; D011506:Proteins; C492169:Sel1h protein, mouse; D008071:Lipoprotein Lipase