Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, China; Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Pharmacol Res. 2021 May;167:105524. doi: 10.1016/j.phrs.2021.105524. Epub 2021 Mar 2.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, by increasing hepatic low density lipoprotein (LDL) receptor (LDLR) levels, has emerged as a strategy to reduce atherosclerosis by lowering circulating very low density lipoprotein (VLDL)-cholesterol. We hypothesized that the therapeutic effectiveness of PCSK9 inhibition can be increased by accelerating the generation of VLDL remnants, which typically have a high affinity for the LDLR. Therefore, we aimed to investigate whether accelerating lipolytic processing of VLDL by brown fat activation can further lower (V)LDL and reduce atherosclerosis on top of PCSK9 inhibition. APOE*3-Leiden.CETP mice were fed a Western-type diet and treated with the anti-PCSK9 antibody alirocumab or saline. After 2 weeks, both groups of mice were randomized to receive either the selective β3-adrenergic receptor (AR) agonist CL316,243 to activate brown fat or saline for 3 additional weeks to evaluate VLDL clearance or 12 additional weeks to analyze atherosclerosis development. β3-AR agonism and alirocumab combined decreased (V)LDL-cholesterol compared to alirocumab alone, which was explained by an accelerated plasma clearance of VLDL-cholesteryl esters that were mainly taken up by the liver. In addition, the combination promoted the transfer of VLDL-phospholipids to HDL to a higher extent than alirocumab alone, accompanied by higher plasma HDL-cholesterol levels and increased cholesterol efflux capacity. Consequently, combination treatment largely reduced atherosclerotic lesion area compared to vehicle. Together, β3-AR agonism enhances the lipoprotein-modulating effects of alirocumab to further improve dyslipidemia and non-significantly further attenuate atherosclerosis development. Our findings demonstrate that brown fat activation may enhance the therapeutic effects of PCSK9 inhibition in dyslipidemia.
前蛋白转化酶枯草溶菌素 9（PCSK9）抑制通过增加肝脏低密度脂蛋白（LDL）受体（LDLR）水平，成为降低循环极低密度脂蛋白（VLDL）-胆固醇以减少动脉粥样硬化的一种策略。我们假设通过加速产生VLDL 残粒，其通常对 LDLR 具有高亲和力，可以增强 PCSK9 抑制的治疗效果。因此，我们旨在研究通过激活棕色脂肪加速 VLDL 的脂肪分解处理是否可以进一步降低（V）LDL 并在 PCSK9 抑制的基础上减少动脉粥样硬化。载脂蛋白 E*3-Leiden.CETP 小鼠喂食西方饮食并接受抗 PCSK9 抗体阿利鲁单抗或盐水治疗。2 周后，两组小鼠随机接受选择性β3-肾上腺素能受体（AR）激动剂 CL316,243 激活棕色脂肪或盐水 3 周，以评估 VLDL 清除情况，或 12 周以分析动脉粥样硬化发展情况。β3-AR 激动剂和阿利鲁单抗联合治疗与单独使用阿利鲁单抗相比，降低了（V）LDL-胆固醇，这是由于 VLDL-胆固醇酯的血浆清除速度加快，主要被肝脏摄取。此外，与单独使用阿利鲁单抗相比，联合治疗更能促进 VLDL-磷脂向 HDL 的转移，导致更高的血浆 HDL-胆固醇水平和增加的胆固醇流出能力。因此，与载体相比，联合治疗大大减少了动脉粥样硬化病变面积。总的来说，β3-AR 激动剂增强了阿利鲁单抗的脂蛋白调节作用，进一步改善了血脂异常，并且非显著地进一步减轻了动脉粥样硬化的发展。我们的研究结果表明，棕色脂肪激活可能增强 PCSK9 抑制在血脂异常中的治疗效果。
