Transcriptomics

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


ABSTRACT: 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. Sel1Lflox/flox mice were crossed with adiponectin promoter driven Cre mice to create adipose tissue-specific Sel1L-/- mice. Male wildtype C57Bl/6 mice and adipose tissue-specific Sel1l-/- mice were fed a high fat diet (Research Diets D12492) for 5 weeks. Adipose tissue was excised and used for microarray analysis.

ORGANISM(S): Mus musculus  

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

PROVIDER: E-GEOD-56918 | ArrayExpress | 2015-05-18

SECONDARY ACCESSION(S): GSE56918PRJNA244933

REPOSITORIES: GEO, ArrayExpress

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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-me  ...[more]

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