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

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.Sel1L是内质网相关降解（endoplasmic reticulum-associated degradation, ERAD）通路中E3泛素连接酶Hrd1的衔接蛋白，但其细胞特异性的生理功能仍未明确。本研究发现，脂肪细胞特异性Sel1L敲除小鼠可抵抗饮食诱导的肥胖，并表现出餐后高甘油三酯血症。从机制层面而言，我们的数据证实，Sel1L对脂蛋白脂酶（lipoprotein lipase, LPL）的分泌具有关键调控作用，且该功能不依赖于其在Hrd1介导的ERAD及内质网稳态中所发挥的作用。进一步的生化分析显示，Sel1L可与由LPL及脂酶成熟因子1（lipase-maturation factor 1, LMF1）组成的LPL成熟复合物发生物理相互作用并稳定该复合物。在Sel1L缺失的情况下，LPL会滞留于内质网中，并易于形成蛋白质聚集体，此类聚集体可通过自噬介导的降解途径被清除。Sel1L介导的LPL分泌调控机制在其他表达LPL的细胞类型中同样存在，例如心肌细胞与巨噬细胞。综上，本研究揭示了Sel1L在LPL分泌及系统性脂质代谢中的全新功能。本研究将Sel1Lflox/flox小鼠与脂联素启动子驱动的Cre重组酶小鼠杂交，构建得到脂肪组织特异性Sel1L敲除（Sel1l-/-）小鼠。将雄性野生型C57Bl/6小鼠及脂肪组织特异性Sel1l-/-小鼠饲喂Research Diets公司D12492型号高脂饲料，持续5周。收取脂肪组织并用于微阵列分析（microarray analysis）。