Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, UW Medicine Diabetes Institute (V.K., Y.H., F.K., M.S.-A., J.E.K., B.S., J.W.H., T.V., K.E.B.).
Keenan Centre for Biomedical Research, St. Michael's Hospital, Toronto, Canada (T.W.W.H., W.L.L.).
Circ Res. 2024 Jul 5;135(2):335-349. doi: 10.1161/CIRCRESAHA.123.323100. Epub 2024 Jun 3.
Individuals with type 1 diabetes (T1D) generally have normal or even higher HDL (high-density lipoprotein)-cholesterol levels than people without diabetes yet are at increased risk for atherosclerotic cardiovascular disease (CVD). Human HDL is a complex mixture of particles that can vary in cholesterol content by >2-fold. To investigate if specific HDL subspecies contribute to the increased atherosclerosis associated with T1D, we created mouse models of T1D that exhibit human-like HDL subspecies. We also measured HDL subspecies and their association with incident CVD in a cohort of people with T1D.
We generated LDL receptor-deficient () mouse models of T1D expressing human APOA1 (apolipoprotein A1). mice exhibited the main human HDL subspecies. We also generated T1D mice expressing CETP (cholesteryl ester transfer protein), which had lower concentrations of large HDL subspecies versus mice not expressing CETP. HDL particle concentrations and sizes and proteins involved in lipoprotein metabolism were measured by calibrated differential ion mobility analysis and targeted mass spectrometry in the mouse models of T1D and in a cohort of individuals with T1D. Endothelial transcytosis was analyzed by total internal reflection fluorescence microscopy.
Diabetic mice were severely hyperglycemic and hyperlipidemic and had markedly elevated plasma APOB levels versus nondiabetic littermates but were protected from the proatherogenic effects of diabetes. Diabetic mice expressing CETP lost the atheroprotective effect and had increased lesion necrotic core areas and APOB accumulation, despite having lower plasma APOB levels. The detrimental effects of low concentrations of larger HDL particles in diabetic mice expressing CETP were not explained by reduced cholesterol efflux. Instead, large HDL was more effective than small HDL in preventing endothelial transcytosis of LDL mediated by scavenger receptor class B type 1. Finally, in humans with T1D, increased concentrations of larger HDL particles relative to APOB100 negatively predicted incident CVD independently of HDL-cholesterol levels.
Our results suggest that the balance between APOB lipoproteins and the larger HDL subspecies contributes to atherosclerosis progression and incident CVD in the setting of T1D and that larger HDLs exert atheroprotective effects on endothelial cells rather than by promoting macrophage cholesterol efflux.
1 型糖尿病（T1D）患者的高密度脂蛋白胆固醇（HDL-C）水平通常与非糖尿病患者相当或更高，但发生动脉粥样硬化性心血管疾病（ASCVD）的风险增加。人类 HDL 是一种复杂的颗粒混合物，其胆固醇含量可相差 2 倍以上。为了研究特定的 HDL 亚类是否有助于增加与 T1D 相关的动脉粥样硬化，我们构建了具有人类样 HDL 亚类的 T1D 小鼠模型。我们还在 T1D 患者队列中测量了 HDL 亚类及其与 ASCVD 发病的相关性。
我们构建了表达人载脂蛋白 A1（apoA1）的 LDL 受体缺陷（）T1D 小鼠模型。这些小鼠表现出主要的人类 HDL 亚类。我们还构建了表达胆固醇酯转移蛋白（CETP）的 T1D 小鼠，与不表达 CETP 的小鼠相比，它们的大 HDL 亚类浓度较低。通过校准的差速离子迁移分析和靶向质谱法，在 T1D 小鼠模型和 T1D 患者队列中测量了 HDL 颗粒浓度和大小以及脂蛋白代谢相关的蛋白。通过全内反射荧光显微镜分析内皮细胞转胞吞作用。
与非糖尿病同窝仔相比，糖尿病 小鼠表现出严重的高血糖和高血脂，且血浆 APOB 水平显著升高，但对糖尿病的致动脉粥样硬化作用具有保护作用。表达 CETP 的糖尿病 小鼠失去了这种抗动脉粥样硬化作用，且病变坏死核心面积增加，APOB 蓄积增加，尽管其血浆 APOB 水平较低。尽管糖尿病表达 CETP 的小鼠的大 HDL 颗粒浓度降低，但胆固醇流出减少并不能解释大 HDL 颗粒的有害作用。相反，大 HDL 比小 HDL 更能有效预防 LDL 介导的内皮细胞转胞吞作用，这种作用由清道夫受体 B 型 1 介导。最后，在 T1D 患者中，与 APOB100 相比，较大 HDL 颗粒浓度的增加与 ASCVD 发病呈负相关，独立于 HDL-C 水平。
我们的研究结果表明，APOB 脂蛋白与较大的 HDL 亚类之间的平衡有助于 T1D 患者的动脉粥样硬化进展和 ASCVD 发病，较大的 HDL 对内皮细胞发挥抗动脉粥样硬化作用，而不是通过促进巨噬细胞胆固醇流出。
