Departments of Medicine University of California Los Angeles, Los Angeles, CA 90095.
Departments of Medicine University of California Los Angeles, Los Angeles, CA 90095.
J Lipid Res. 2018 Apr;59(4):706-713. doi: 10.1194/jlr.M083832. Epub 2018 Feb 15.
Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1), an endothelial cell protein, binds LPL in the subendothelial spaces and transports it to the capillary lumen. In mice, LPL remains stranded in the subendothelial spaces, causing hypertriglyceridemia, but how mice respond to metabolic stress (e.g., cold exposure) has never been studied. In wild-type mice, cold exposure increases LPL-mediated processing of triglyceride-rich lipoproteins (TRLs) in brown adipose tissue (BAT), providing fuel for thermogenesis and leading to lower plasma triglyceride levels. We suspected that defective TRL processing in mice might impair thermogenesis and blunt the fall in plasma triglyceride levels. Indeed, mice exhibited cold intolerance, but the effects on plasma triglyceride levels were paradoxical. Rather than falling, the plasma triglyceride levels increased sharply (from ∼4,000 to ∼15,000 mg/dl), likely because fatty acid release by peripheral tissues drives hepatic production of TRLs that cannot be processed. We predicted that the sharp increase in plasma triglyceride levels would not occur in mice, where LPL activity is higher and baseline plasma triglyceride levels are lower. Indeed, the plasma triglyceride levels in mice fell during cold exposure. Metabolic studies revealed increased levels of TRL processing in the BAT of mice.
糖基磷脂酰肌醇锚定高密度脂蛋白结合蛋白 1（GPIHBP1）是一种内皮细胞蛋白，它在内皮细胞下腔与 LPL 结合，并将其运送到毛细血管腔。在 GPIHBP1 敲除小鼠中，LPL 仍然滞留在内皮细胞下腔，导致高甘油三酯血症，但代谢应激（如寒冷暴露）如何影响 GPIHBP1 敲除小鼠一直没有被研究过。在野生型小鼠中，寒冷暴露会增加棕色脂肪组织（BAT）中 LPL 介导的富含甘油三酯脂蛋白（TRLs）的处理，为产热提供燃料，导致血浆甘油三酯水平降低。我们推测 GPIHBP1 敲除小鼠中 TRL 的处理缺陷可能会损害产热并使血浆甘油三酯水平下降。事实上，GPIHBP1 敲除小鼠表现出不耐寒，但对血浆甘油三酯水平的影响却是矛盾的。血浆甘油三酯水平并没有下降，反而急剧上升（从约 4000 到约 15000mg/dl），可能是因为外周组织释放的脂肪酸促使肝脏产生不能被处理的 TRL。我们预测在 LPL 活性更高且基础血浆甘油三酯水平更低的 GPIHBP1 敲除小鼠中，不会出现血浆甘油三酯水平的急剧上升。事实上，在寒冷暴露期间，GPIHBP1 敲除小鼠的血浆甘油三酯水平下降了。代谢研究显示 GPIHBP1 敲除小鼠 BAT 中的 TRL 处理水平升高。
