標題: Kruppel-Like Factor 4 Regulation of Cholesterol-25-Hydroxylase and Liver X Receptor Mitigates Atherosclerosis Susceptibility
作者: Li, Zhao
Martin, Marcy
Zhang, Jin
Huang, Hsi-Yuan
Bai, Liang
Zhang, Jiao
Kang, Jian
He, Ming
Li, Jie
Maurya, Mano R.
Gupta, Shakti
Zhou, Guangjin
Sangwung, Panjamaporn
Xu, Yong-Jiang
Lei, Ting
Huang, Hsien-Da
Jain, Mohit
Jain, Mukesh K.
Subramaniam, Shankar
Shyy, John Y. -J.
生物科技學系
生物資訊及系統生物研究所
Department of Biological Science and Technology
Institude of Bioinformatics and Systems Biology
關鍵字: atherosclerosis;cholesterol;endothelial cells;inflammation;macrophages;shear stress
公開日期: 3-十月-2017
摘要: BACKGROUND: Atherosclerosis is a multifaceted inflammatory disease involving cells in the vascular wall (eg, endothelial cells [ECs]), as well as circulating and resident immunogenic cells (eg, monocytes/macrophages). Acting as a ligand for liver X receptor (LXR), but an inhibitor of SREBP2 (sterol regulatory element-binding protein 2), 25-hydroxycholesterol, and its catalyzing enzyme cholesterol-25-hydroxylase (Ch25h) are important in regulating cellular inflammatory status and cholesterol biosynthesis in both ECs and monocytes/macrophages. METHODS: Bioinformatic analyses were used to investigate RNA-sequencing data to identify cholesterol oxidation and efflux genes regulated by Kruppel-like factor 4 (KLF4). In vitro experiments involving cultured ECs and macrophages and in vivo methods involving mice with Ch25h ablation were then used to explore the atheroprotective role of KLF4-Ch25h/LXR. RESULTS: Vasoprotective stimuli increased the expression of Ch25h and LXR via KLF4. The KLF4-Ch25h/LXR homeostatic axis functions through suppressing inflammation, evidenced by the reduction of inflammasome activity in ECs and the promotion of M1 to M2 phenotypic transition in macrophages. The increased atherosclerosis in apolipoprotein E-/-/Ch25h(-/-)mice further demonstrates the beneficial role of the KLF4-Ch25h/LXR axis in vascular function and disease. CONCLUSIONS: KLF4 transactivates Ch25h and LXR, thereby promoting the synergistic effects between ECs and macrophages to protect against atherosclerosis susceptibility.
URI: http://dx.doi.org/10.1161/CIRCULATIONAHA.117.027462
http://hdl.handle.net/11536/143855
ISSN: 0009-7322
DOI: 10.1161/CIRCULATIONAHA.117.027462
期刊: CIRCULATION
Volume: 136
起始頁: 1315
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