Impaired hepatic insulin signalling in PON2-deficient mice: a novel role for the PON2/apoE axis on the macrophage inflammatory response.
Impaired hepatic insulin signalling in PON2-deficient mice: a novel role for the PON2/apoE axis on the macrophage inflammatory response.
复制标题
PON2缺陷型小鼠中肝胰岛素信号受损受损：PON2/APOE轴对巨噬细胞炎症反应的新作用。
DOI：
10.1042/bj20101891
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发表时间：
2011-05-15
期刊：
影响因子：
--
通讯作者：
Reddy ST
中科院分区：
文献类型：
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作者：
Bourquard N;Ng CJ;Reddy ST
肝脏葡萄糖代谢受到氧化应激和促炎刺激的强烈影响。 PON2（对氧磷酶 2）是一种具有不确定抗氧化特性的酶，可预防动脉粥样硬化。 PON2 缺陷 (PON2-def) 小鼠的肝脏氧化应激升高，同时 PON2 缺陷巨噬细胞的炎症反应加剧。在本文中，我们证明 PON2 缺陷与抑制性胰岛素介导的肝脏 IRS-1（胰岛素受体底物-1）磷酸化有关。出乎意料的是，我们观察到 PON2-def/apoE（载脂蛋白 E）−/− 小鼠的肝脏 IRS-1 磷酸化状态相对于 apoE−/− 小鼠有显着改善。来自 PON2-def 和 PON2-def/apoE−/− 小鼠的活化巨噬细胞培养物分泌的因子足以以类似于体内观察到的方式调节培养的肝细胞中的胰岛素信号传导。我们发现，PON2-def/apoE−/− 小鼠中胰岛素信号传导的保护作用与巨噬细胞促炎介质产生的改变直接相关，但与细胞内氧化应激水平升高无关。我们进一步证明，PON2-def/apoE−/− 小鼠巨噬细胞炎症反应的调节是通过 NO 和 ONOO−（过氧亚硝酸盐）形成平衡的变化介导的。我们的结果表明，PON2 在肝脏胰岛素信号传导中发挥着重要作用，并强调了巨噬细胞介导的炎症反应对肝脏胰岛素敏感性的影响。
Hepatic glucose metabolism is strongly influenced by oxidative stress and pro-inflammatory stimuli. PON2 (paraoxonase 2), an enzyme with undefined antioxidant properties, protects against atherosclerosis. PON2-deficient (PON2-def) mice have elevated hepatic oxidative stress coupled with an exacerbated inflammatory response from PON2-deficient macrophages. In the present paper, we demonstrate that PON2 deficiency is associated with inhibitory insulin-mediated phosphorylation of hepatic IRS-1 (insulin receptor substrate-1). Unexpectedly, we observed a marked improvement in the hepatic IRS-1 phosphorylation state in PON2-def/apoE (apolipoprotein E)−/− mice, relative to apoE−/− mice. Factors secreted from activated macrophage cultures derived from PON2-def and PON2-def/apoE−/− mice are sufficient to modulate insulin signalling in cultured hepatocytes in a manner similar to that observed in vivo. We show that the protective effect on insulin signalling in PON2-def/apoE−/− mice is directly associated with altered production of macrophage proinflammatory mediators, but not elevated intracellular oxidative stress levels. We further present evidence that modulation of the macrophage inflammatory response in PON2-def/apoE−/− mice is mediated by a shift in the balance of NO and ONOO− (peroxynitrite) formation. Our results demonstrate that PON2 plays an important role in hepatic insulin signalling and underscores the influence of macrophage-mediated inflammatory response on hepatic insulin sensitivity.