1 型糖尿病患者的 APOB 脂蛋白和大高密度脂蛋白失衡会导致动脉粥样硬化。

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2024-07-05 Epub Date: 2024-06-03 DOI:10.1161/CIRCRESAHA.123.323100
Vishal Kothari, Tse W W Ho, Ainara G Cabodevilla, Yi He, Farah Kramer, Masami Shimizu-Albergine, Jenny E Kanter, Janet Snell-Bergeon, Edward A Fisher, Baohai Shao, Jay W Heinecke, Jacob O Wobbrock, Warren L Lee, Ira J Goldberg, Tomas Vaisar, Karin E Bornfeldt
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We also measured HDL subspecies and their association with incident CVD in a cohort of people with T1D.</p><p><strong>Methods: </strong>We generated LDL receptor-deficient (<i>Ldlr</i><sup><i>-/-</i></sup>) mouse models of T1D expressing human APOA1 (apolipoprotein A1). <i>Ldlr</i><sup><i>-/-</i></sup><i>APOA1</i><sup><i>Tg</i></sup> mice exhibited the main human HDL subspecies. We also generated <i>Ldlr</i><sup><i>-/-</i></sup><i>APOA1</i><sup><i>Tg</i></sup> 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. 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引用次数: 0

摘要

背景:1 型糖尿病(T1D)患者的 HDL(高密度脂蛋白)胆固醇水平通常正常,甚至高于非糖尿病患者,但他们罹患动脉粥样硬化性心血管疾病(CVD)的风险却增加了。人类高密度脂蛋白是一种复杂的颗粒混合物,其胆固醇含量可相差 2 倍以上。为了研究特定的高密度脂蛋白亚种是否会导致与 T1D 相关的动脉粥样硬化加重,我们创建了表现出类似人类高密度脂蛋白亚种的 T1D 小鼠模型。我们还在一组 T1D 患者中测量了高密度脂蛋白亚种及其与心血管疾病的关系:我们建立了表达人类 APOA1(载脂蛋白 A1)的低密度脂蛋白受体缺陷(Ldlr-/-)T1D 小鼠模型。Ldlr-/-APOA1Tg小鼠表现出主要的人类高密度脂蛋白亚种。我们还培育了表达 CETP(胆固醇酯转移蛋白)的 Ldlr-/-APOA1Tg T1D 小鼠,与不表达 CETP 的小鼠相比,这些小鼠的大型 HDL 亚种浓度较低。在 T1D 小鼠模型和 T1D 患者队列中,通过校准差分离子迁移率分析和靶向质谱法测量了高密度脂蛋白颗粒的浓度和大小以及参与脂蛋白代谢的蛋白质。通过全内反射荧光显微镜分析了内皮细胞的转囊现象:结果:与非糖尿病小鼠相比,糖尿病 Ldlr-/-APOA1Tg 小鼠有严重的高血糖和高脂血症,血浆 APOB 水平明显升高,但却不受糖尿病致动脉粥样硬化效应的影响。表达 CETP 的糖尿病 Ldlr-/-APOA1Tg 小鼠失去了动脉粥样硬化保护作用,尽管其血浆 APOB 水平较低,但病变坏死核心区域和 APOB 积累增加。在表达 CETP 的糖尿病小鼠体内,低浓度的较大 HDL 颗粒所产生的有害影响并不能用胆固醇外流减少来解释。相反,大的高密度脂蛋白比小的高密度脂蛋白更能有效阻止由 B 类清道夫受体 1 型介导的低密度脂蛋白的内皮细胞转运。最后,在患有 T1D 的人群中,相对于 APOB100 而言,大高密度脂蛋白浓度的增加对心血管疾病的发生有负面预测作用,而与高密度脂蛋白胆固醇水平无关:我们的研究结果表明,APOB脂蛋白和较大型高密度脂蛋白亚种之间的平衡有助于T1D患者动脉粥样硬化的进展和心血管疾病的发生,较大型高密度脂蛋白对内皮细胞具有动脉粥样硬化保护作用,而不是通过促进巨噬细胞胆固醇外流。
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Imbalance of APOB Lipoproteins and Large HDL in Type 1 Diabetes Drives Atherosclerosis.

Background: 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.

Methods: We generated LDL receptor-deficient (Ldlr-/-) mouse models of T1D expressing human APOA1 (apolipoprotein A1). Ldlr-/-APOA1Tg mice exhibited the main human HDL subspecies. We also generated Ldlr-/-APOA1Tg 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.

Results: Diabetic Ldlr-/-APOA1Tg 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 Ldlr-/-APOA1Tg 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.

Conclusions: 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.

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来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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