Background and Aims. Apolipoprotein A-I (ApoA-I), the main component of high-density lipoprotein (HDL), not only promotes reverse cholesterol transport (RCT) in atherosclerosis but also increases insulin secretion in pancreatic β-cells, suggesting that interventions which raise HDL levels may be beneficial in diabetes-associated cardiovascular disease (CVD). Previously, we showed that TNF-related apoptosis-inducing ligand (TRAIL) deletion in Apolipoprotein Eknockout (Apoe^-/-) mice results in diabetes-accelerated atherosclerosis in response to a “Western” diet. Here, we sought to identify whether reconstituted HDL (rHDL) could improve features of diabetes-associated CVD in Trail^-/-Apoe^-/- mice. Methods and Results. Trail^-/-Apoe^-/- and Apoe^-/- mice on a “Western” diet for 12 weeks received 3 weekly infusions of either PBS (vehicle) or rHDL (containing ApoA-I (20 mg/kg) and 1-palmitoyl-2-linoleoyl phosphatidylcholine). Administration of rHDL reduced total plasma cholesterol, triglyceride, and glucose levels in Trail^-/-Apoe^-/- but not in Apoe^-/- mice, with no change in weight gain observed. rHDL treatment also improved glucose clearance in response to insulin and glucose tolerance tests. Immunohistological analysis of pancreata revealed increased insulin expression/production and a reduction in macrophage infiltration in mice with TRAIL deletion. Furthermore, atherosclerotic plaque size in Trail^-/-Apoe^-/- mice was significantly reduced associating with increased expression of the M2 macrophage marker CD206, suggesting HDL's involvement in the polarization of macrophages. rHDL also increased vascular mRNA expression of RCT transporters, ABCA1 and ABCG1, in Trail^-/-Apoe^-/- but not in Apoe^-/- mice. Conclusions. rHDL improves features of diabetes-associated atherosclerosis in mice. These findings support the therapeutic potential of rHDL in the treatment of atherosclerosis and associated diabetic complications. More studies are warranted to understand rHDL’s mechanism of action.

中文翻译：

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HDL 改善胆固醇和葡萄糖稳态并减少糖尿病相关动脉粥样硬化的动脉粥样硬化

背景和目标。载脂蛋白 AI (ApoA-I) 是高密度脂蛋白 (HDL) 的主要成分，不仅可以促进动脉粥样硬化中的胆固醇逆向转运 (RCT)，还可以增加胰腺β细胞的胰岛素分泌，这表明提高 HDL 水平的干预措施可能对糖尿病相关的心血管疾病 (CVD) 有益。之前，我们发现载脂蛋白 E敲除 ( Apoe ^-/- ) 小鼠中 TNF 相关的凋亡诱导配体 (TRAIL) 缺失会导致糖尿病加速的动脉粥样硬化，以响应“西方”饮食。在这里，我们试图确定重建的 HDL (rHDL) 是否可以改善Trail ^-/- Apoe中糖尿病相关 CVD 的特征^-/-老鼠。方法和结果。Trail ^-/- Apoe ^-/-和Apoe ^-/-小鼠采用“西方”饮食 12 周，每周接受 3 次 PBS（载体）或 rHDL（含有 ApoA-I (20 mg/kg) 和 1-棕榈酰-2-亚油酰磷脂酰胆碱）。rHDL 的给药降低了Trail ^-/- Apoe ^{-/- 中的}总血浆胆固醇、甘油三酯和葡萄糖水平，但没有降低 Apoe ^-/-小鼠，没有观察到体重增加的变化。rHDL 治疗还改善了响应胰岛素和葡萄糖耐量测试的葡萄糖清除率。胰腺的免疫组织学分析显示，在 TRAIL 缺失的小鼠中，胰岛素表达/产生增加，巨噬细胞浸润减少。此外，Trail ^-/- Apoe ^-/-小鼠的动脉粥样硬化斑块大小显着降低，这与 M2 巨噬细胞标记物 CD206 的表达增加有关，这表明 HDL 参与了巨噬细胞的极化。的rHDL也增加RCT转运，ABCA1和ABCG1，在血管mRNA表达径^{- / -}的ApoE ^{- / -}但不是在APOE ^{- / -}小鼠. 结论。rHDL 改善了小鼠糖尿病相关动脉粥样硬化的特征。这些发现支持 rHDL 在治疗动脉粥样硬化和相关糖尿病并发症方面的治疗潜力。需要更多的研究来了解 rHDL 的作用机制。