CYP450表氧化酶/EET代谢途径通过HIF-1α减轻肥胖小鼠脂肪炎症  

CYP450 epoxygenase/EET pathway attenuates adipose inflammation of obese mice through HIF-1α

作　　者：焉晓乘 牟维娜 强晔 赵蕙琛 孙琦 姚晓敏 张玉超 刘元涛 YAN Xiao-cheng;MU Wei-na;QIANG Ye;ZHAO Hui-chen;SUN Qi;YAO Xiaomin;ZHANG Yu-chao;LIU Yuan-tao(Department of Endocrinology,Qingdao Municipal Hospital Affiliated to Qingdao University School of Medicine,Qingdao 266011,China;Department of Endocrinology,Jiaozhou Central Hospital of Qingdao,Qingdao 266300,China;Department of Endocrinology,Rizhao People's Hospital,Rizhao 276826,China)

机构地区：[1]青岛大学医学院附属青岛市市立医院内分泌科,山东青岛266011 [2]青岛市胶州中心医院内分泌科,山东青岛266300 [3]日照市人民医院内分泌科,山东日照276826

出　　处：《中国病理生理杂志》2020年第9期1661-1666,共6页Chinese Journal of Pathophysiology

基　　金：青岛市创新领军人才项目(No.16-8-3-24-zhc)。

摘　　要：目的:比较细胞色素P450(CYP450)表氧化酶在肥胖小鼠与正常小鼠内脏脂肪组织中的表达差异,观察外源性环氧二十碳三烯酸(EET)对肥胖小鼠胰岛素抵抗、炎症及血管再生的影响。方法:以C57BL/6Cnc小鼠为研究对象,经高脂饮食建立小鼠肥胖模型。成模后,将肥胖小鼠随机分为肥胖组(n=10)、EET组(n=10)和EET拮抗剂14,15-环氧二十碳-5(Z)-烯酸(EEZE)组(n=10),分别腹腔注射生理盐水、11,12-EET和14,15-EEZE。普通饮食饲养的非肥胖C57BL/6Cnc小鼠作为正常对照组(n=10)。Western blot检测小鼠内脏脂肪组织CYP2J2(一种CYP450表氧化酶)及低氧诱导因子1α(HIF-1α)的蛋白表达水平;ELISA检测血清胰岛素及炎症因子水平;免疫组化检测内脏脂肪组织毛细血管密度。结果:与正常小鼠相比,肥胖小鼠胰岛素抵抗指数上升,内脏脂肪CYP2J2表达降低,HIF-1α表达升高,血清中炎症因子水平增高,内脏脂肪中血管样组织减少(均P<0.05)。外源性11,12-EET可以显著降低肥胖小鼠胰岛素抵抗指数、内脏脂肪组织中HIF-1α表达和血清炎症因子水平,促进内脏脂肪血管样组织生成(均P<0.05)。结论:EET可减轻肥胖小鼠胰岛素抵抗、脂肪组织缺氧和炎症,并促进血管生成。AIM:To investigate the effects of cytochrome P450(CYP450)epoxygenase/epoxyeicosatrienoic acid(EET)pathway on insulin resistance in obese mice,and to explore the possible mechanisms.METHODS:High-fat diet-induced obesity model was established in C57BL/6Cnc mice,and the obese mice were randomly divided into 3 groups,including obesity group(treated with saline;n=10),EET group(treated with 11,12-EET;n=10)and EET inhibi tor 14,15-epoxyeicosa-5(Z)-enoic acid(EEZE)group(n=10).Normal C57BL/6Cnc mice(n=10)treated with saline served as control.Protein expression of CYP2J2(one of CYP450 epoxygenases)and hypoxia-inducible factor-1α(HIF-1α)was measured by Western blot.Vessel-like structure was detected by immunofluorescence staining.The serum levels of insulin,tumor necrosis factor-α(TNF-α),interleukin(IL)-1β,IL-6 and monocyte chemoattractant protein-1(MCP-1)were measured by ELISA.RESULTS:In obese mice,homeostasis model assessment of insulin resistance(HOMAIR)values were increased,the protein level of CYP2J2 was reduced,and the protein level of HIF-1α was increased in adi pose tissues as compared with the controls(P<0.05).The serum levels of MCP-1,IL-1β,IL-6 and TNF-α were also sig nificantly increased in obese mice(P<0.05).After treatment with 11,12-EET,the HOMA-IR values were decreased compared with vehicle-treated obese mice,HIF-1αexpression levels were decreased in the adipose tissue,and the serum levels of MCP-1,IL-1β,IL-6 and TNF-α were reduced(P<0.05).Immunohistochemical results of adipose tissue from vehicle-treated obese mice showed a marked decrease in vessel-like structures(CD31-positive)compared with normal con trol mice(P<0.05).EET treatment significantly increased the newly formed vessel-like structures in the visceral adipose tissues of obese mice as compared with vehicle-treated obese mice(P<0.05).CONCLUSION:High-fat diet-induced obesity and insulin resistance are closely related to the CYP450 pathway.Exogenous EETs effectively decrease obesity-in duced insulin resistance possibly through pro-angioge

关 键 词：肥胖 胰岛素抵抗 环氧二十碳三烯酸 细胞色素P450表氧化酶 低氧诱导因子1Α 炎症 

分 类 号：R589.2[医药卫生—内分泌] R363.2[医药卫生—内科学]