OBJECTIVE We tested the hypothesis that enlarged, dysfunctional HDL (high-density lipoprotein) particles contribute to the augmented atherosclerosis susceptibility associated with SR-BI (scavenger receptor BI) deficiency in mice. Approach and Results: We eliminated the ability of HDL particles to fully mature by targeting PLTP (phospholipid transfer protein) functionality. Particle size of the HDL population was almost fully normalized in male and female SR-BI×PLTP double knockout mice. In contrast, the plasma unesterified cholesterol to cholesteryl ester ratio remained elevated. The PLTP deficiency-induced reduction in HDL size in SR-BI knockout mice resulted in a normalized aortic tissue oxidative stress status on Western-type diet. Atherosclerosis susceptibility was-however-only partially reversed in double knockout mice, which can likely be attributed to the fact that they developed a metabolic syndrome-like phenotype characterized by obesity, hypertriglyceridemia, and a reduced glucose tolerance. Mechanistic studies in chow diet-fed mice revealed that the diminished glucose tolerance was probably secondary to the exaggerated postprandial triglyceride response. The absence of PLTP did not affect LPL (lipoprotein lipase)-mediated triglyceride lipolysis but rather modified the ability of VLDL (very low-density lipoprotein)/chylomicron remnants to be cleared from the circulation by the liver through receptors other than SR-BI. As a result, livers of double knockout mice only cleared 26% of the fractional dose of [14C]cholesteryl oleate after intravenous VLDL-like particle injection. CONCLUSIONS We have shown that disruption of PLTP-mediated HDL maturation reduces SR-BI deficiency-driven atherosclerosis susceptibility in mice despite the induction of proatherogenic metabolic complications in the double knockout mice.

中文翻译：

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磷脂转移蛋白介导的高密度脂蛋白成熟的破坏，尽管发生了意外的代谢并发症，却降低了清道夫受体BI缺乏引起的动脉粥样硬化的易感性。

目的我们检验了假说，即功能失调的HDL（高密度脂蛋白）颗粒增大，导致小鼠中与SR-BI（清道夫受体BI）缺乏相关的动脉粥样硬化易感性增加。方法和结果：我们通过靶向PLTP（磷脂转移蛋白）功能消除了HDL颗粒完全成熟的能力。在雄性和雌性SR-BI×PLTP双敲除小鼠中，HDL群体的粒径几乎完全标准化。相反，血浆未酯化胆固醇与胆甾醇酯的比率保持升高。SR-BI基因敲除小鼠中PLTP缺乏引起的HDL大小减少导致西方型饮食上的主动脉组织氧化应激状态正常化。然而，在双敲除小鼠中，动脉粥样硬化易感性仅被部分逆转，这可能归因于他们形成了以肥胖，高甘油三酯血症和降低的葡萄糖耐量为特征的代谢综合征样表型。对通过饮食喂养的小鼠进行的机理研究表明，葡萄糖耐量降低可能是由于餐后甘油三酯反应过度引起的。不存在PLTP不会影响LPL（脂蛋白脂肪酶）介导的甘油三酸酯脂解作用，但会改变VLDL（极低密度脂蛋白）/乳糜微粒残留物通过SR-BI以外的受体从肝脏中清除的能力。结果，在静脉内注射VLDL样颗粒后，双敲除小鼠的肝脏仅清除了[14C]胆固醇油酸酯分数剂量的26％。