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

Abstract

SUMMARY Sel1L is an essential adaptor protein for the E3 ligase Hrd1 in the endoplasmic reticulum-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), independently of its role in Hrd1-mediated ERAD and ER homeostasis. 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 form 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.

ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis

“…Our data show that mammalian SEL1L-HRD1 ERAD is responsible for the clearance of misfolded proAVP in the ER and thereby ERAD deficiency is not necessarily associated with elevated cell death is further supported by recent reports of ERAD-deficient adipocytes (25,26), B cells (27), and colonic epithelium (21). We speculate that cells with compromised ERAD function may adapt in a number of ways including autophagy, reprogramming of BiP or other ER chaperone expression, and/or sequestering of misfolded proteins into "nontoxic" amyloid aggregates (51) in order to reset the parameters of ER homeostasis and thereby allow cells to survive for an extended period of time.…”

“…Thus far, studies of ERAD in a cell type-specific context lag behind those of the UPR, but evidence published to date suggests that the physiological role of Sel1L-Hrd1 ERAD can be UPR independent, depending on the specific substrate(s) found in specific cell types (20,21,(25)(26)(27)(46)(47)(48). In this study, we showed that ER retention of proAVP occurs early and coincides with the initiation of diabetes insipidus in Sel1L-deficient mice.…”

“…Germline Sel1L or Hrd1 deficiency is embryonically lethal in mice (23,24), and acute global loss of Sel1L or Hrd1 in adult mice leads to premature death within 2 to 3 weeks (20,23), suggesting that Sel1L and Hrd1 are indispensable for both development and postnatal survival (11). Recent studies of cell type-specific Sel1L-Hrd1 deficiency in adipocytes (25,26), B cells (27), and colonic epithelium (21) have delineated the physiological importance of ERAD in these various tissues and identified several endogenous substrates (11), including IRE1α of the unfolded protein response (UPR) in many cell types (20); lipoprotein lipase and PGC1β in adipocytes (25,26); and pre-B cell receptor in developing B cells (27). However, the role of ERAD in neuroendocrine cells has not been explored.…”

Endoplasmic reticulum quality control in cancer: Friend or foe

“…In the absence of Sel1L , the development of embryonic pancreatic epithelial cell was blocked [70]. Using inducible and adipocyte-specific Sel1L -deficient mouse and cell models, we recently demonstrated that Sel1L plays a critical role in the stabilization of HRD1 protein in mammals [69, 71] and that the Sel1L –Hrd1 complex plays a critical role in mammalian ERAD, ER homeostasis and survival in vivo [69]. Acute loss of Sel1L in adult mice causes premature lethality and severe pathologies of secretory tissues with striking abnormalities of the ER structure integrity, suggesting a crucial role of Sel1L in secretory cell types in particular.…”

MiR-27b Impairs Adipocyte Differentiation of Human Adipose Tissue-Derived Mesenchymal Stem Cells by Targeting LPL

“…Lipoprotein lipase (LPL), most abundantly expressed in adipose tissue, macrophages, heart and skeletal muscle, acts as a gatekeeper for the entry of fatty acids into tissues and controls systemic lipid partitioning, which is essential for energy homeostasis of the body [18]. Human LPL plays a significant role in regulating triglyceride (TG) levels by hydrolyzing TGs in TG-rich lipoproteins as the first step in their metabolism [19].…”