The Lipid Research Laboratory, Technion Faculty of Medicine, the Rappaport Family Institute for Research in the Medical Sciences, Rambam Medical Center, Haifa, Israel.
Biofactors. 2012 Jul-Aug;38(4):292-9. doi: 10.1002/biof.1021. Epub 2012 Jun 4.
We analyzed, for the first time, both in vitro and in vivo, the effect of very low density lipoprotein (VLDL), or of pure triglycerides, on high-density lipoprotein (HDL)-associated paraoxonase1 (PON1) catalytic activities. Incubation of serum or HDL from healthy subjects with VLDL (0-330 μg protein/mL) significantly decreased serum PON1 lactonase or arylesterase activities by up to 11% or 24%, and HDL-associated PON1 lactonase or arylesterase activities by up to 32% or 46%, respectively, in a VLDL dose-dependent manner. VLDL (0-660 μg protein/mL) also inhibited recombinant PON1 (rePON1) lactonase or arylesterase activities by up to 20% or 42%, respectively. Similar inhibitory effect was noted upon rePON1 incubation with pure triglyceride emulsion. Bezafibrate therapy to three hypertriglyceridemic patients (400 mg/day, for one month) significantly decreased serum triglyceride concentration by 67%, and increased serum HDL cholesterol levels by 48%. PON1 arylesterase or paraoxonase activities in the patients' HDL fractions after drug therapy were significantly increased by 86-88%, as compared to PON1 activities before treatment. Similarly, HDL-PON1 protein levels significantly increased after bezafibrate therapy. Finally, bezafibrate therapy improved HDL biological activity, as HDL obtained after drug therapy showed increased ability to induce cholesterol efflux from J774A.1 macrophages, by 19%, as compared to HDL derived before therapy. We thus conclude that VLDL triglycerides inhibit PON1 catalytic activities, and bezafibrate therapy significantly improved HDL-PON1 catalytic and biological activities.
我们首次分析了极低密度脂蛋白（VLDL）或纯甘油三酯对高密度脂蛋白（HDL）相关对氧磷酶 1（PON1）催化活性的体外和体内影响。将健康受试者的血清或 HDL 与 VLDL（0-330μg 蛋白/mL）孵育，可使血清 PON1 内酯酶或芳基酯酶活性分别降低 11%或 24%，HDL 相关的 PON1 内酯酶或芳基酯酶活性分别降低 32%或 46%，呈 VLDL 剂量依赖性。VLDL（0-660μg 蛋白/mL）也可使重组 PON1（rePON1）内酯酶或芳基酯酶活性分别降低 20%或 42%。在用纯甘油三酯乳液孵育 rePON1 时也观察到类似的抑制作用。给予三位高甘油三酯血症患者（每天 400mg，为期一个月）贝扎贝特治疗，可使血清甘油三酯浓度降低 67%，HDL 胆固醇水平升高 48%。与治疗前相比，患者 HDL 级分中的 PON1 芳基酯酶或对氧磷酶活性在药物治疗后分别增加了 86-88%。同样，贝扎贝特治疗后 HDL-PON1 蛋白水平也显著增加。最后，贝扎贝特治疗改善了 HDL 的生物学活性，因为与治疗前相比，药物治疗后获得的 HDL 诱导 J774A.1 巨噬细胞胆固醇流出的能力增加了 19%。因此，我们得出结论，VLDL 甘油三酯抑制 PON1 催化活性，贝扎贝特治疗可显著改善 HDL-PON1 的催化和生物学活性。
