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Krüppel-like factor 14 inhibits atherosclerosis via mir-27a-mediated down-regulation of lipoprotein lipase expression in vivo

  • Author Footnotes
    1 These authors contributed equally to this work.
    Wei Xie
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China

    Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, 421001, Hunan, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Liang Li
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China

    Department of Pathophysiology, University of South China, Hengyang, 421001, Hunan, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Duo Gong
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China
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  • Min Zhang
    Affiliations
    Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China
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  • Yun-Cheng Lv
    Affiliations
    Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, 421001, Hunan, China
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  • Dong-ming Guo
    Affiliations
    Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, 421001, Hunan, China
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  • Zhen-Wang Zhao
    Affiliations
    Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China
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  • Xi-Long Zheng
    Affiliations
    Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, The University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta, Canada, T2N 4N1

    Key Laboratory of Molecular Targets & Clinical Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
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  • Da-Wei Zhang
    Affiliations
    Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Alberta, Canada
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  • Xiao-Yan Dai
    Affiliations
    Guangdong Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
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  • Wei-Dong Yin
    Correspondence
    Corresponding author. Institute of Cardiovascular Research, University of South China, Hengyang, Hunan, 421001, China.
    Affiliations
    Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China
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  • Chao-Ke Tang
    Correspondence
    Corresponding author. Institute of Cardiovascular Research, University of South China, Hengyang, Hunan, 421001, China.
    Affiliations
    Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China
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  • Author Footnotes
    1 These authors contributed equally to this work.

      Highlights

      • KLF14 inhibits proinflammatory cytokines and lipid accumulation in macrophages via binding to the promoter of miR-27a.
      • MiR-27a-mediated LPL downregulation participates in the inhibitory effect of KLF14 on inflammation and lipid accumulation.
      • Gypenosides, a KLF14 activator, delays the development of atherosclerosis in apoE−/− mice.

      Abstract

      Background and aims

      Krüppel-like factor 14 (KLF14) is known to play a role in atherosclerosis, but the underlying mechanisms are still largely unknown. The aim of our study was to explore the effects of KLF14 on lipid metabolism and inflammatory response, providing a potential target for lowering the risk of atherosclerosis-causing disease.

      Methods and results

      mRNA and protein levels of KLF14 were significantly decreased in oxidized low-density lipoprotein (oxLDL)-treated macrophages and in the atherosclerotic lesion area. Chromatin immunoprecipitation (ChIP) and luciferase reporter gene assays were used to confirm that KLF14 positively regulated miR-27a expression by binding to its promoter. We also found that KLF14 could restored appropriate cellular lipid homeostasis and inflammatory responses via negatively regulating lipoprotein lipase (LPL) expression in THP1-derived macrophages through miR-27a. In addition, gypenosides (GP), a KLF14 activator, delayed the development of atherosclerosis in apolipoprotein E deficient (apoE−/−) mice.

      Conclusions

      KLF14 plays an antiatherogenic role via the miR-27a-dependent down-regulation of LPL and subsequent inhibition of proinflammatory cytokine secretion and lipid accumulation.

      Graphical abstract

      Keywords

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