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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB_1) receptors in the regenerating liver
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Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB_1) receptors in the regenerating liver

机译：再生肝中大麻素合成的过度激活和通过1型大麻素（CB_1）受体调节细胞周期进程

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摘要

The mammalian liver regenerates upon tissue loss, which induces quiescent hepatocytes to enter the cell cycle and undergo limited replication under the control of multiple hormones, growth factors, and cytokines. Endocannabinoids acting via cannabinoid type 1 receptors (CB_1R) promote neural progenitor cell proliferation, and in the liver they promote lipogenesis. These findings suggest the involvement of CB_1R in the control of liver regeneration. Here we report that mice lacking CB_1R globally or in hepatocytes only and wild-type mice treated with a CB_1R antagonist have a delayed pro-liferative response to two-thirds partial hepatectomy (PHX). In wild-type mice, PHX leads to increased hepatic expression of CB-1R and hyperactivation of the biosynthesis of the endocannabinoid anandamide in the liver via an in vivo pathway involving conjugation of arachidonic acid and ethanolamine by fatty-acid amide hy-drolase. In wild-type but not CB_1R-/- mice, PHX induces robust up-regulation of key cell-cycle proteins involved in mitotic progression, including cyclin-dependent kinase 1 (Cdk1), cyclin B2, and theirtran-scriptional regulator forkhead box protein M1 (FoxM1), as revealed by ultrahigh-throughput RNA sequencing and pathway analysis and confirmed by real-time PCR and Western blot analyses. Treatment of wild-type mice with anandamide induces similar changes mediated via activation of the PI3K/Akt pathway. We conclude that activation of hepatic CB_1R by newly synthesized anandamide promotes liver regeneration by controlling the expression of cell-cycle regulators that drive M phase progression.
机译：哺乳动物肝脏在组织丧失时再生，这导致静止的肝细胞进入细胞周期并在多种激素，生长因子和细胞因子的控制下进行有限的复制。通过1型大麻素受体（CB_1R）起作用的内源性大麻素促进神经祖细胞增殖，在肝脏中它们促进脂肪生成。这些发现表明CB_1R参与肝再生的控制。在这里，我们报道小鼠缺乏CB_1R全局或仅在肝细胞中，而用CB_1R拮抗剂治疗的野生型小鼠对三分之二的部分肝切除术（PHX）的增殖反应延迟。在野生型小鼠中，PHX导致肝脏中CB-1R的肝表达增加，并通过体内途径（包括脂肪酸酰胺水合酶与花生四烯酸和乙醇胺的结合）使肝脏中的内源性大麻素的生物合成过度活化。在野生型而非CB_1R-/-小鼠中，PHX诱导参与有丝分裂进程的关键细胞周期蛋白（包括细胞周期蛋白依赖性激酶1（Cdk1），细胞周期蛋白B2及其转录调控因子叉头盒蛋白）强烈上调M1（FoxM1），通过超高通量RNA测序和途径分析显示，并通过实时PCR和Western印迹分析证实。用anandamide处理野生型小鼠会诱导类似的变化，这些变化是通过激活PI3K / Akt途径介导的。我们得出的结论是，通过新合成的anandamide激活肝CB_1R，可通过控制驱动M期进程的细胞周期调节因子的表达来促进肝脏再生。

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    Bani Mukhopadhyay; Resat Cinar; Shi Yin; Jie Liu; Joseph Tam; Grzegorz Godlewski; Judith Harvey-White; Isioma Mordi; Benjamin F. Cravatt; Sophie Lotersztajn; Bin Gao; Qiaoping Yuan; Kornel Schuebel; David Goldman; George Kunos;

  • 作者单位

    Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Liver Biology, National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Bethesda, MD 20892;

    Scripps Institute, La Jolla, CA 92037;

    lnstitut National de la Sante et de la Recherche Medicale U955,Universite Paris XII Val de Marne, Creteil, France;

    Laboratory of Liver Biology, National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Bethesda, MD 20892;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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