Xiao Changting, Watanabe Takehiko, Zhang Yi, Trigatti Bernardo, Szeto Linda, Connelly Phil W, Marcovina Santica, Vaisar Tomas, Heinecke Jay W, Lewis Gary F
Department of Medicine and Physiology, University of Toronto, Ontario, Canada.
Circ Res. 2008 Jul 18;103(2):159-66. doi: 10.1161/CIRCRESAHA.108.178756. Epub 2008 Jun 12.
A low level of high-density lipoprotein (HDL) cholesterol is characteristic of insulin resistance and hypertriglyceridemia and likely contributes to the increased risk of cardiovascular disease associated with these conditions. One pathway involves enhanced clearance of lipolytically modified HDL particles, but the underlying mechanisms remain poorly understood. Here, we examine the effect of triglyceride enrichment and hepatic lipase hydrolysis on HDL binding, internalization, and degradation in cultured liver and kidney cells. Maximal binding of remnant HDL (HDL enriched with triglycerides followed by hepatic lipase hydrolysis), but not binding affinity, was markedly higher than native and triglyceride-rich HDL in both HepG2 cells and HEK293 cells. Compared with native and triglyceride-rich HDL, remnant HDL was internalized to a greater extent in both cell types and was more readily degraded in HEK293 cells. The increased binding of remnant HDL was not mediated by the low-density lipoprotein receptor or scavenger receptor class B type I (SR-BI), because enhanced remnant HDL binding was observed in low-density lipoprotein receptor-deficient cells with or without SR-BI overexpression. Disruption of cell surface heparan sulfate proteoglycans or blockage of apolipoprotein E-mediated lipoprotein binding also did not abolish the enhanced remnant HDL binding. Our observations indicate that remodeling of triglyceride-enriched HDL by hepatic lipase may result in enhanced binding, internalization, and degradation in tissues involved in HDL catabolism, contributing to rapid clearance and overall lowering of plasma HDL cholesterol in insulin resistance and hypertriglyceridemia.
高密度脂蛋白（HDL）胆固醇水平低是胰岛素抵抗和高甘油三酯血症的特征，可能会增加与这些病症相关的心血管疾病风险。一种途径涉及脂解修饰的HDL颗粒清除增强，但其潜在机制仍知之甚少。在这里，我们研究了甘油三酯富集和肝脂肪酶水解对培养的肝细胞和肾细胞中HDL结合、内化和降解的影响。在HepG2细胞和HEK293细胞中，残余HDL（富含甘油三酯后经肝脂肪酶水解的HDL）的最大结合量（而非结合亲和力）明显高于天然HDL和富含甘油三酯的HDL。与天然HDL和富含甘油三酯的HDL相比，残余HDL在两种细胞类型中的内化程度更高，并且在HEK293细胞中更容易降解。残余HDL结合增加不是由低密度脂蛋白受体或B类I型清道夫受体（SR-BI）介导的，因为在有或没有SR-BI过表达的低密度脂蛋白受体缺陷细胞中都观察到残余HDL结合增强。细胞表面硫酸乙酰肝素蛋白聚糖的破坏或载脂蛋白E介导的脂蛋白结合的阻断也没有消除残余HDL结合增强。我们的观察结果表明，肝脂肪酶对富含甘油三酯的HDL进行重塑可能导致参与HDL分解代谢的组织中结合、内化和降解增强，有助于胰岛素抵抗和高甘油三酯血症患者血浆HDL胆固醇的快速清除和总体降低。
