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The ER-associated degradation adaptor protein Sel1L regulates LPL secretion and lipid metabolism.

Sha H., Sun S., Francisco A.B., Ehrhardt N., Xue Z., Liu L., Lawrence P., Mattijssen F., Guber R.D., Panhwar M.S., Brenna J.T., Shi H., Xue B., Kersten S., Bensadoun A., Peterfy M., Long Q., Qi L.

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.

Cell Metab. 20:458-470(2014) [PubMed] [Europe PMC]

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