Department of Pharmacological and Biomolecular Sciences (M.B., S.M., A.C., E.F., F.B., R.O., A.L., G.D.N., G.C.), Università degli Studi di Milano, Italy.
Department of Biosciences (M.C., D.H.), Università degli Studi di Milano, Italy.
Arterioscler Thromb Vasc Biol. 2022 Jul;42(7):839-856. doi: 10.1161/ATVBAHA.122.317790. Epub 2022 May 19.
HDL (high-density lipoprotein) and its major protein component, apoA-I (apolipoprotein A-I), play a unique role in cholesterol homeostasis and immunity. ApoA-I deficiency in hyperlipidemic, atheroprone mice was shown to drive cholesterol accumulation and inflammatory cell activation/proliferation. The present study was aimed at investigating the impact of apoA-I deficiency on lipid deposition and local/systemic inflammation in normolipidemic conditions.
ApoE deficient mice, apoE/apoA-I double deficient (DKO) mice, DKO mice overexpressing human apoA-I, and C57Bl/6J control mice were fed normal laboratory diet until 30 weeks of age. Plasma lipids were quantified, atherosclerosis development at the aortic sinus and coronary arteries was measured, skin ultrastructure was evaluated by electron microscopy. Blood and lymphoid organs were characterized through histological, immunocytofluorimetric, and whole transcriptome analyses.
DKO were characterized by almost complete HDL deficiency and by plasma total cholesterol levels comparable to control mice. Only DKO showed xanthoma formation and severe inflammation in the skin-draining lymph nodes, whose transcriptome analysis revealed a dramatic impairment in energy metabolism and fatty acid oxidation pathways. An increased presence of CD4 T effector memory cells was detected in blood, spleen, and skin-draining lymph nodes of DKO. A worsening of atherosclerosis at the aortic sinus and coronary arteries was also observed in DKO versus apoE deficient. Human apoA-I overexpression in the DKO background was able to rescue the skin phenotype and halt atherosclerosis development.
HDL deficiency, in the absence of hyperlipidemia, is associated with severe alterations of skin morphology, aortic and coronary atherosclerosis, local and systemic inflammation.
高密度脂蛋白（HDL）及其主要蛋白成分载脂蛋白 A-I（apoA-I）在胆固醇稳态和免疫中发挥独特作用。高脂血症、动脉粥样硬化易感小鼠的 apoA-I 缺乏会导致胆固醇积累和炎症细胞激活/增殖。本研究旨在研究 apoA-I 缺乏对正常脂质条件下脂质沉积和局部/全身炎症的影响。
apoE 缺陷小鼠、apoE/apoA-I 双缺陷（DKO）小鼠、过表达人 apoA-I 的 DKO 小鼠和 C57Bl/6J 对照小鼠在正常实验室饮食中喂养至 30 周龄。定量检测血浆脂质，测量主动脉窦和冠状动脉的动脉粥样硬化发展情况，通过电子显微镜评估皮肤超微结构。通过组织学、免疫细胞荧光和全转录组分析来描述血液和淋巴器官。
DKO 的特征是几乎完全缺乏 HDL，血浆总胆固醇水平与对照小鼠相当。只有 DKO 出现黄瘤形成和皮肤引流淋巴结严重炎症，其转录组分析显示能量代谢和脂肪酸氧化途径严重受损。在 DKO 的血液、脾脏和皮肤引流淋巴结中检测到 CD4 T 效应记忆细胞的存在增加。与 apoE 缺陷小鼠相比，DKO 的主动脉窦和冠状动脉动脉粥样硬化也有所恶化。DKO 背景下的人 apoA-I 过表达能够挽救皮肤表型并阻止动脉粥样硬化的发展。
在没有高脂血症的情况下，HDL 缺乏与皮肤形态、主动脉和冠状动脉粥样硬化、局部和全身炎症的严重改变有关。
