外泌体蛋白抑制巨噬细胞脂质蓄积并通过 p38/Elk-1 通路上调 ABCA1 和 ABCG1 的表达从而减轻动脉粥样硬化负担。
Asprosin inhibits macrophage lipid accumulation and reduces atherosclerotic burden by up-regulating ABCA1 and ABCG1 expression via the p38/Elk-1 pathway.
机构信息
The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China.
Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China.
出版信息
J Transl Med. 2022 Jul 28;20(1):337. doi: 10.1186/s12967-022-03542-0.
BACKGROUND
Asprosin, a newly discovered adipokine, is a C-terminal cleavage product of profibrillin. Asprosin has been reported to participate in lipid metabolism and cardiovascular disease, but its role in atherogenesis remains elusive.
METHODS
Asprosin was overexpressed in THP-1 macrophage-derived foam cells and apoE mice using the lentiviral vector. The expression of relevant molecules was determined by qRT-PCR and/or western blot. The intracellular lipid accumulation was evaluated by high-performance liquid chromatography and Oil red O staining. HE and Oil red O staining was employed to assess plaque burden in vivo. Reverse cholesterol transport (RCT) efficiency was measured using [H]-labeled cholesterol.
RESULTS
Exposure of THP-1 macrophages to oxidized low-density lipoprotein down-regulated asprosin expression. Lentivirus-mediated overexpression of asprosin promoted cholesterol efflux and inhibited lipid accumulation in THP-1 macrophage-derived foam cells. Mechanistic analysis revealed that asprosin overexpression activated p38 and stimulated the phosphorylation of ETS-like transcription factor (Elk-1) at Ser383, leading to Elk-1 nuclear translocation and the transcriptional activation of ATP binding cassette transporters A1 (ABCA1) and ABCG1. Injection of lentiviral vector expressing asprosin diminished atherosclerotic lesion area, increased plaque stability, improved plasma lipid profiles and facilitated RCT in apoE mice. Asprosin overexpression also increased the phosphorylation of p38 and Elk-1 as well as up-regulated the expression of ABCA1 and ABCG1 in the aortas.
CONCLUSION
Asprosin inhibits lipid accumulation in macrophages and decreases atherosclerotic burden in apoE mice by up-regulating ABCA1 and ABCG1 expression via activation of the p38/Elk-1 signaling pathway.
背景
Asprosin 是一种新发现的脂肪因子，是原纤维蛋白的 C 端裂解产物。Asprosin 已被报道参与脂质代谢和心血管疾病，但它在动脉粥样硬化形成中的作用仍不清楚。
方法
使用慢病毒载体在 THP-1 巨噬细胞源性泡沫细胞和载脂蛋白 E（apoE）小鼠中过表达 asprosin。通过 qRT-PCR 和/或 Western blot 测定相关分子的表达。通过高效液相色谱和油红 O 染色评估细胞内脂质积累。采用 HE 和油红 O 染色法评估体内斑块负担。使用 [H]-标记胆固醇测量胆固醇逆向转运（RCT）效率。
结果
暴露于氧化型低密度脂蛋白的 THP-1 巨噬细胞下调 asprosin 的表达。慢病毒介导的 asprosin 过表达促进了 THP-1 巨噬细胞源性泡沫细胞中的胆固醇流出，并抑制了脂质积累。机制分析表明，asprosin 过表达激活了 p38，并刺激 ETS 样转录因子（Elk-1）在 Ser383 处的磷酸化，导致 Elk-1 核转位和 ATP 结合盒转运体 A1（ABCA1）和 ABCG1 的转录激活。注射表达 asprosin 的慢病毒载体减少了 apoE 小鼠的动脉粥样硬化病变面积，增加了斑块稳定性，改善了血浆脂质谱，并促进了 RCT。Asprosin 过表达还增加了 p38 和 Elk-1 的磷酸化，上调了主动脉中 ABCA1 和 ABCG1 的表达。
结论
Asprosin 通过激活 p38/Elk-1 信号通路，上调 ABCA1 和 ABCG1 的表达，抑制巨噬细胞中的脂质积累，并减少 apoE 小鼠的动脉粥样硬化负担。
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