CYP2J2 attenuates metabolic dysfunction in diabetic mice by reducing hepatic inflammation via the PPARγ
CYP2J2 attenuates metabolic dysfunction in diabetic mice by reducing hepatic inflammation via the PPARγ
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DOI：
10.1152/ajpendo.00118.2014
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发表时间：
2015-01-15
影响因子：
5.1
通讯作者：
Wang, Dao Wen
中科院分区：
文献类型：
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作者：
Li, Rui;Xu, Xizhen;Wang, Dao Wen
环氧二十碳三烯酸（Epoxyeicosatrienoic acids，E10）和花生四烯酸衍生的细胞色素P450（P450）环氧合酶代谢产物具有多种生物学效应，包括在血管系统中的抗炎特性。越来越多的证据表明，2型糖尿病的炎症是胰岛素抵抗发展的关键组成部分。在这项研究中，我们研究了在糖尿病db/db小鼠和培养的肝细胞（HepG 2）中，β-环氧合酶的表达和外源性雌二醇是否可以减轻胰岛素抵抗。在体内，CYP 2 J2的表达和伴随的Eketamine的增加减弱了胰岛素抵抗，如通过血浆葡萄糖水平、葡萄糖耐量试验、胰岛素耐量试验和高胰岛素血症正葡萄糖钳夹研究所确定的。CYP 2 J2表达减少了肝脏中促炎细胞因子的产生，包括CRP、IL-6、IL-β和TNF α，并减少了肝脏中巨噬细胞的浸润。CYP 2 J2表达还通过降低肝细胞中NF-κ B和MAPK活化来降低促炎信号级联的活化。有趣的是，CYP 2 J2表达和外源性EET治疗增加了葡萄糖摄取，并在体内和体外激活了胰岛素信号级联反应，表明CYP 2 J2代谢产物在葡萄糖稳态中发挥作用。此外，CYP 2 J2表达上调了PPAR γ，这已被证明可诱导脂肪形成，从而减轻糖尿病中观察到的血脂异常。所有的研究结果表明，CYP 2 J2表达通过抑制NF-κ B和MAPK信号通路以及激活PPAR γ来减轻糖尿病表型和胰岛素抵抗。
Epoxyeicosatrienoic acids (EETs) and arachidonic acid-derived cytochrome P450 (CYP) epoxygenase metabolites have diverse biological effects, including anti-inflammatory properties in the vasculature. Increasing evidence suggests that inflammation in type 2 diabetes is a key component in the development of insulin resistance. In this study, we investigated whether CYP epoxygenase expression and exogenous EETs can attenuate insulin resistance in diabetic db/db mice and in cultured hepatic cells (HepG2). In vivo, CYP2J2 expression and the accompanying increase in EETs attenuated insulin resistance, as determined by plasma glucose levels, glucose tolerance test, insulin tolerance test, and hyperinsulinemic euglycemic clamp studies. CYP2J2 expression reduced the production of proinflammatory cytokines in liver, including CRP, IL-6, IL-beta, and TNF alpha, and decreased the infiltration of macrophages in liver. CYP2J2 expression also decreased activation of proinflammatory signaling cascades by decreasing NF-kappa B and MAPK activation in hepatocytes. Interestingly, CYP2J2 expression and exogenous EET treatment increased glucose uptake and activated the insulin-signaling cascade both in vivo and in vitro, suggesting that CYP2J2 metabolites play a role in glucose homeostasis. Furthermore, CYP2J2 expression upregulated PPAR gamma, which has been shown to induce adipogenesis, which attenuates dyslipidemias observed in diabetes. All of the findings suggest that CYP2J2 expression attenuates the diabetic phenotype and insulin resistance via inhibition of NF-kappa B and MAPK signaling pathways and activation of PPAR gamma.