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

被引:102
|
作者
Sha, Haibo [1 ]
Sun, Shengyi [2 ]
Francisco, Adam B. [3 ]
Ehrhardt, Nicole [4 ]
Xue, Zhen [1 ]
Liu, Lei [1 ]
Lawrence, Peter [1 ]
Mattijssen, Frits [5 ]
Guber, Robert D. [1 ]
Panhwar, Muhammad S. [6 ]
Brenna, J. Thomas [1 ]
Shi, Hang [7 ]
Xue, Bingzhong [7 ]
Kersten, Sander [1 ,5 ]
Bensadoun, Andre [1 ]
Peterfy, Miklos [4 ,8 ]
Long, Qiaoming [9 ]
Qi, Ling [1 ,2 ]
机构
[1] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA
[2] Cornell Univ, Grad Program Biochem Mol & Cell Biol, Ithaca, NY 14853 USA
[3] Cornell Univ, Dept Anim Sci, Ithaca, NY 14853 USA
[4] Cedars Sinai Med Ctr, Med Genet Res Inst, Dept Biomed Sci, Los Angeles, CA 90048 USA
[5] Wageningen Univ, Nutr Metab & Genom Grp, NL-6703 HD Wageningen, Netherlands
[6] Weill Cornell Med Coll Qatar, Doha, Qatar
[7] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA
[8] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA
[9] Soochow Univ, Coll Med, Lab Anim Res Ctr, Suzhou 215006, Jiangsu, Peoples R China
基金
美国国家科学基金会;
关键词
RETICULUM-ASSOCIATED-DEGRADATION; ENDOPLASMIC-RETICULUM; LIPOPROTEIN-LIPASE; CAENORHABDITIS-ELEGANS; MEMBRANE-PROTEIN; STRESS; DEFICIENCY; MATURATION; DISEASE; LIVER;
D O I
10.1016/j.cmet.2014.06.015
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
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.
引用
收藏
页码:458 / 470
页数:13
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