Sorting Nexin 10 Mediates Metabolic Reprogramming of Macrophages in Atherosclerosis Through the Lyn-Dependent TFEB Signaling Pathway
Sorting Nexin 10 Mediates Metabolic Reprogramming of Macrophages in Atherosclerosis Through the Lyn-Dependent TFEB Signaling Pathway
复制标题
分选 Nexin 10 通过 Lyn 依赖性 TFEB 信号通路介导动脉粥样硬化中巨噬细胞的代谢重编程
DOI：
10.1161/circresaha.119.315516
复制
发表时间：
2020-04
影响因子：
20.1
通讯作者：
Shen Xiaoyan
中科院分区：
文献类型：
--
作者：
You Yan;Bao Wei-Lian;Zhang Su-Lin;Li Hai-Dong;Li Hui;Dang Wen-Zhen;Zou Si-Li;Cao Xin-Yue;Wang Xu;Liu Li-Xin;Jiang Hualiang;Qu Le-Feng;Zheng Mingyue;Shen Xiaoyan
补充数字内容可在文本中找到。基本原理：SNX10（分选连接蛋白10）已被报道在调节巨噬细胞功能和脂质代谢中发挥关键作用。目的：探讨SNX10在动脉粥样硬化性疾病中的作用及其机制。方法和结果：比较SNX10在人健康血管和颈动脉粥样硬化斑块中的表达。骨髓细胞特异性SNX10敲除小鼠与APOE −/−（载脂蛋白E）背景杂交，并监测动脉粥样硬化（高胆固醇饮食诱导）16周。我们发现SNX10的表达在人类和APOE −/−小鼠主动脉标本的动脉粥样硬化病变中增加。髓样细胞特异性SNX10缺陷（Δ敲除[KO]）减弱了APOE −/−小鼠的动脉粥样硬化进展。Δ KO小鼠外周血和动脉粥样硬化病变中的抗炎单核细胞/巨噬细胞数量增加。体外实验表明，SNX10缺陷通过中断CD36的内化来抑制泡沫细胞形成，这需要SNX10和Lyn-AKT（蛋白激酶B）的相互作用。SNX10缺陷导致的Lyn-AKT激活减少促进了TFEB（转录因子EB）的核转位，从而增强了溶酶体生物合成和LAL（溶酶体酸性脂肪酶）活性，导致游离脂肪酸增加，为线粒体脂肪酸氧化提供燃料。这进一步促进了巨噬细胞的重编程并向抗炎表型转变。结论：我们的数据首次证明SNX10通过Lyn-Akt-TFEB信号通路和巨噬细胞重编程之间先前未知的联系在饮食诱导的动脉粥样硬化形成中起关键作用，表明SNX10可能是动脉粥样硬化治疗的潜在有希望的治疗靶点。
Supplemental Digital Content is available in the text. Rationale: SNX10 (sorting nexin 10) has been reported to play a critical role in regulating macrophage function and lipid metabolism. Objective: To investigate the precise role of SNX10 in atherosclerotic diseases and the underlying mechanisms. Methods and Results: SNX10 expression was compared between human healthy vessels and carotid atherosclerotic plaques. Myeloid cell-specific SNX10 knockdown mice were crossed onto the APOE−/− (apolipoprotein E) background and atherogenesis (high-cholesterol diet-induced) was monitored for 16 weeks. We found that SNX10 expression was increased in atherosclerotic lesions of aortic specimens from humans and APOE−/− mice. Myeloid cell-specific SNX10 deficiency (Δ knockout [KO]) attenuated atherosclerosis progression in APOE−/− mice. The population of anti-inflammatory monocytes/macrophages was increased in the peripheral blood and atherosclerotic lesions of ΔKO mice. In vitro experiments showed that SNX10 deficiency-inhibited foam cell formation through interrupting the internalization of CD36, which requires the interaction of SNX10 and Lyn-AKT (protein kinase B). The reduced Lyn-AKT activation by SNX10 deficiency promoted the nuclear translocation of TFEB (transcription factor EB), thereby enhanced lysosomal biogenesis and LAL (lysosomal acid lipase) activity, resulting in an increase of free fatty acids to fuel mitochondrial fatty acid oxidation. This further promoted the reprogramming of macrophages and shifted toward the anti-inflammatory phenotype. Conclusions: Our data demonstrate for the first time that SNX10 plays a crucial role in diet-induced atherogenesis via the previously unknown link between the Lyn-Akt-TFEB signaling pathway and macrophage reprogramming, suggest that SNX10 may be a potentially promising therapeutic target for atherosclerosis treatment.
登录
查看更多内容
影响因子：
20.1
作者：
Sarrazy V;Viaud M;Westerterp M;Ivanov S;Giorgetti-Peraldi S;Guinamard R;Gautier EL;Thorp EB;De Vivo DC;Yvan-Charvet L
通讯作者：
Yvan-Charvet L
分选连接蛋白在心血管疾病中的新作用
影响因子：
6
作者：
Yang Jian;Villar Van Anthony M.;Rozyyev Selim;Jose Pedro A;Zeng Chuyu
通讯作者：
Zeng Chuyu
影响因子：
30.5
作者：
Koelwyn GJ;Corr EM;Erbay E;Moore KJ
通讯作者：
Moore KJ
影响因子：
11.8
作者：
Heit, Bryan;Kim, Hani;Cosio, Gabriela;Castano, Diana;Collins, Richard;Lowell, Clifford A.;Kain, Kevin C.;Trimble, William S.;Grinstein, Sergio
通讯作者：
Grinstein, Sergio
影响因子：
30.5
作者：
通讯作者：
--