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VASP Increases Hepatic Fatty Acid Oxidation by Activating AMPK in Mice

机译:VASP通过激活小鼠中的AMPK来增加肝脂肪酸氧化

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摘要

Activation of AMP-activated protein kinase (AMPK) signaling reduces hepatic steatosis and hepatic insulin resistance; however, its regulatory mechanisms are not fully understood. In this study, we sought to determine whether vasodilator-stimulated phosphoprotein (VASP) signaling improves lipid metabolism in the liver and, if so, whether VASP's effects are mediated by AMPK. We show that disruption of VASP results in significant hepatic steatosis as a result of significant impairment of fatty acid oxidation, VLDL-triglyceride (TG) secretion, and AMPK signaling. Overexpression of VASP in hepatocytes increased AMPK phos-phorylation and fatty acid oxidation and reduced hepatocyte TG accumulation; however, these responses were suppressed in the presence of an AMPK inhibitor. Restoration of AMPK phosphor-ylation by administration of 5-aminoimidazole-4-carboxamide riboside in Vasp~(-/-) mice reduced hepatic steatosis and normalized fatty acid oxidation and VLDL-TG secretion. Activation of VASP by the phosphodiesterase-5 inhibitor, sildenafil, in db/db mice reduced hepatic steatosis and increased phosphorylated (p-)AMPK and p-acetyl CoA carboxylase. In Vasp~(-/-) mice, however, sildendafil treatment did not increase p-AMPK or reduce hepatic TG content. These studies identify a role of VASP to enhance hepatic fatty acid oxidation by activating AMPK and to promote VLDL-TG secretion from the liver.
机译:AMP激活的蛋白激酶(AMPK)信号的激活减少了肝脂肪变性和肝胰岛素抵抗。但是,其监管机制尚未完全了解。在这项研究中,我们试图确定血管舒张剂刺激的磷蛋白(VASP)信号传导是否能改善肝脏中的脂质代谢,如果是,则可以确定AMPK是否介导了VASP的作用。我们表明,由于脂肪酸氧化,VLDL-甘油三酸酯(TG)分泌和AMPK信号转导的严重损害,VASP的破坏导致严重的肝脂肪变性。肝细胞中VASP的过表达增加了AMPK磷酸化和脂肪酸氧化,并减少了肝细胞TG的积累。但是,在AMPK抑制剂存在下,这些反应受到抑制。通过在Vasp〜(-/-)小鼠中施用5-氨基咪唑-4-羧酰胺核糖核苷来恢复AMPK磷酸化,可减少肝脂肪变性,使脂肪酸氧化和VLDL-TG分泌正常化。 db / db小鼠中磷酸二酯酶5抑制剂sildenafil对VASP的激活减少了肝脂肪变性并增加了磷酸化(p-)AMPK和对乙酰CoA羧化酶。然而,在Vasp-(-/-)小鼠中,sildendafil治疗并未增加p-AMPK或降低肝TG含量。这些研究确定了VASP通过激活AMPK增强肝脂肪酸氧化并促进肝脏VLDL-TG分泌的作用。

著录项

  • 来源
    《Diabetes》 |2013年第6期|1913-1922|共10页
  • 作者单位

    Department of Medicine, University of Washington, Seattle, Washington,Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington;

    Department of Medicine, University of Washington, Seattle, Washington,Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington;

    Department of Medicine, University of Washington, Seattle, Washington,Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington;

    Department of Medicine, University of Washington, Seattle, Washington,Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington;

    Department of Medicine, University of Washington, Seattle, Washington,Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington;

    Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington;

    Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington,Department of Pathology, University of Washington, Seattle, Washington;

    Department of Medicine, University of Washington, Seattle, Washington,Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington,Department of Pathology, University of Washington, Seattle, Washington;

    Department of Surgery, University of Washington, Seattle, Washington;

    Department of Surgery, University of Washington, Seattle, Washington;

    Department of Medicine, University of Washington, Seattle, Washington,Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington;

    Department of Medicine, University of Washington, Seattle, Washington,Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington;

  • 收录信息 美国《科学引文索引》(SCI);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-18 03:46:25

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