GPR120 facilitates cholesterol efflux in macrophages through activation of AMPK signaling pathway
GPR120 facilitates cholesterol efflux in macrophages through activation of AMPK signaling pathway
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GPR120 通过激活 AMPK 信号通路促进巨噬细胞中的胆固醇流出
DOI：
10.1111/febs.15310
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发表时间：
2020-04-14
期刊：
影响因子：
5.4
通讯作者：
Tang, Weiqing
中科院分区：
文献类型：
--
作者：
An, Tong;Zhang, Xiaoyi;Tang, Weiqing
巨噬细胞胆固醇外流是胆固醇逆向转运的第一步，是高密度脂蛋白介导的动脉粥样硬化保护的重要过程。G蛋白偶联受体(GPR)120作为长链脂肪酸受体，在巨噬细胞中具有抗炎和胰岛素增敏作用。然而，GPR120在巨噬细胞泡沫细胞形成中的作用尚未得到证实，巨噬细胞泡沫细胞是动脉粥样硬化斑块的标志。在本研究中，我们首次发现GPR120被其激动剂GW9508刺激后，THP-1巨噬细胞源性泡沫细胞和Raw264.7巨噬细胞的ATP结合盒转运体(ABC)A1和Abcg1的表达增加，并促进ABCA1和Abcg1介导的胆固醇外流，降低细胞胆固醇酯(CE)含量。此外，在巨噬细胞中，GPR120的激活伴随着AMPK通路的刺激，而GPR120对巨噬细胞胆固醇流出的影响则被AMPK抑制所抵消。此外，抑制GPR120或应用磷脂酶C(PLC)抑制剂、钙离子螯合剂或CaMKK抑制剂可显著降低AMPK活性和ABCA1、Abcg1的表达。由于只有游离胆固醇才能从巨噬细胞流出，我们发现AMPK的激活可以通过上调中性胆固醇酯水解酶的表达来增加中性CES的水解率，并通过激活ULK1来增加酸性CES的水解率。综上所述，这些结果表明GPR120通过激活PLC/Ca~(2+)/CaMKK/AMPK信号通路，促进ABCA1和Abcg1介导的胆固醇外流，诱导CE水解酶，上调巨噬细胞ABCA1和Abcg1的表达。
Cholesterol efflux from macrophages is the initial step of reverse cholesterol transport, an important process for high-density lipoprotein-mediated atheroprotection. G protein-coupled receptor (GPR) 120, which functions as long-chain fatty acid receptor, is well known for its anti-inflammatory and insulin-sensitizing function in macrophages. However, the role of GPR120 on macrophage foam cell formation, the hallmark of atherosclerotic plaques, has not been verified. In this study, we found for the first time that stimulation of GPR120 by its agonist GW9508 elevated the expression of ATP-binding cassette transporters (ABC) A1 and ABCG1 in THP-1 macrophage-derived foam cells and Raw264.7 macrophages, and promoted ABCA1- and ABCG1-mediated cholesterol efflux and reduced cellular cholesteryl ester (CE) content as well. In addition, GPR120 activation was accompanied with the stimulation of AMPK pathway in macrophages; however, the effect of GPR120 on macrophage cholesterol efflux was largely abolished by AMPK inhibition. Moreover, the AMPK activity and the expression of ABCA1 and ABCG1 were markedly abrogated by knockdown of GPR120, or application of phospholipase C (PLC) inhibitor, calcium chelator, or CaMKK inhibitor. Because only free cholesterol can be effluxed from macrophages, we found that activation of AMPK could lead to increase both neutral CEs hydrolysis by upregulation of neutral cholesterol ester hydrolase expression and acid CEs hydrolysis by activation of ULK1. In conclusion, these results demonstrated that GPR120 facilitated ABCA1- and ABCG1-mediated cholesterol efflux through activation of PLC/Ca2+/CaMKK/AMPK signaling pathway, which induced CE hydrolysis and elevated the expression of ABCA1 and ABCG1 in macrophages.