Kruppel-Like Factor 4 Regulation of Cholesterol-25-Hydroxylase and Liver X Receptor Mitigates Atherosclerosis Susceptibility

Zhao  Li; Marcy Martin; Jin Zhang; Hsi-Yuan Huang; Liang Bai; Jiao Zhang; Jian Kang; Ming He; Jie Li; Mano R. Maurya; Shakti Gupta; Guangjin Zhou; Panjamaporn Sangwung; Yong-Jiang Xu; Ting Lei; Hsien-Da Huang; Mohit Jain; Mukesh K. Jain; Shankar Subramaniam; John Y. -J. Shyy

doi:10.1161/CIRCULATIONAHA.117.027462

Kruppel-Like Factor 4 Regulation of Cholesterol-25-Hydroxylase and Liver X Receptor Mitigates Atherosclerosis Susceptibility

Zhao Li, Marcy Martin, Jin Zhang, Hsi-Yuan Huang, Liang Bai, Jiao Zhang, Jian Kang, Ming He, Jie Li, Mano R. Maurya, Shakti Gupta, Guangjin Zhou, Panjamaporn Sangwung, Yong-Jiang Xu, Ting Lei, Hsien-Da Huang, Mohit Jain, Mukesh K. Jain, Shankar Subramaniam, John Y. -J. Shyy

Department of Biological Science and Technology

Research output: Contribution to journal › Article › peer-review

91 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1315-+
Journal	Circulation
Volume	136
Issue number	14
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.117.027462
State	Published - 3 Oct 2017

Keywords

atherosclerosis; cholesterol; endothelial cells; inflammation; macrophages; shear stress

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10.1161/CIRCULATIONAHA.117.027462

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Li, Z., Martin, M., Zhang, J., Huang, H.-Y., Bai, L., Zhang, J., Kang, J., He, M., Li, J., Maurya, M. R., Gupta, S., Zhou, G., Sangwung, P., Xu, Y.-J., Lei, T., Huang, H.-D., Jain, M., Jain, M. K., Subramaniam, S., & Shyy, J. Y. .-J. (2017). Kruppel-Like Factor 4 Regulation of Cholesterol-25-Hydroxylase and Liver X Receptor Mitigates Atherosclerosis Susceptibility. Circulation, 136(14), 1315-+. https://doi.org/10.1161/CIRCULATIONAHA.117.027462

@article{e0a0eb33873644958be9791abf993b6a,

title = "Kruppel-Like Factor 4 Regulation of Cholesterol-25-Hydroxylase and Liver X Receptor Mitigates Atherosclerosis Susceptibility",

abstract = "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.",

keywords = "atherosclerosis; cholesterol; endothelial cells; inflammation; macrophages; shear stress",

author = "Zhao Li and Marcy Martin and Jin Zhang and Hsi-Yuan Huang and Liang Bai and Jiao Zhang and Jian Kang and Ming He and Jie Li and Maurya, {Mano R.} and Shakti Gupta and Guangjin Zhou and Panjamaporn Sangwung and Yong-Jiang Xu and Ting Lei and Hsien-Da Huang and Mohit Jain and Jain, {Mukesh K.} and Shankar Subramaniam and Shyy, {John Y. -J.}",

year = "2017",

month = oct,

day = "3",

doi = "10.1161/CIRCULATIONAHA.117.027462",

language = "English",

volume = "136",

pages = "1315--+",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "14",

}

Li, Z, Martin, M, Zhang, J, Huang, H-Y, Bai, L, Zhang, J, Kang, J, He, M, Li, J, Maurya, MR, Gupta, S, Zhou, G, Sangwung, P, Xu, Y-J, Lei, T, Huang, H-D, Jain, M, Jain, MK, Subramaniam, S & Shyy, JY-J 2017, 'Kruppel-Like Factor 4 Regulation of Cholesterol-25-Hydroxylase and Liver X Receptor Mitigates Atherosclerosis Susceptibility', Circulation, vol. 136, no. 14, pp. 1315-+. https://doi.org/10.1161/CIRCULATIONAHA.117.027462

TY - JOUR

T1 - Kruppel-Like Factor 4 Regulation of Cholesterol-25-Hydroxylase and Liver X Receptor Mitigates Atherosclerosis Susceptibility

AU - Li, Zhao

AU - Martin, Marcy

AU - Zhang, Jin

AU - Huang, Hsi-Yuan

AU - Bai, Liang

AU - Zhang, Jiao

AU - Kang, Jian

AU - He, Ming

AU - Li, Jie

AU - Maurya, Mano R.

AU - Gupta, Shakti

AU - Zhou, Guangjin

AU - Sangwung, Panjamaporn

AU - Xu, Yong-Jiang

AU - Lei, Ting

AU - Huang, Hsien-Da

AU - Jain, Mohit

AU - Jain, Mukesh K.

AU - Subramaniam, Shankar

AU - Shyy, John Y. -J.

PY - 2017/10/3

Y1 - 2017/10/3

N2 - 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.

AB - 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.

KW - atherosclerosis; cholesterol; endothelial cells; inflammation; macrophages; shear stress

U2 - 10.1161/CIRCULATIONAHA.117.027462

DO - 10.1161/CIRCULATIONAHA.117.027462

M3 - Article

SN - 0009-7322

VL - 136

SP - 1315-+

JO - Circulation

JF - Circulation

IS - 14

ER -

Kruppel-Like Factor 4 Regulation of Cholesterol-25-Hydroxylase and Liver X Receptor Mitigates Atherosclerosis Susceptibility

Abstract

Keywords

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