乙醇通过 CYP2E1 途径诱导的氧化应激破坏脂肪细胞中脂联素的分泌。
Ethanol-induced oxidative stress via the CYP2E1 pathway disrupts adiponectin secretion from adipocytes.
机构信息
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
出版信息
Alcohol Clin Exp Res. 2012 Feb;36(2):214-22. doi: 10.1111/j.1530-0277.2011.01607.x. Epub 2011 Sep 6.
BACKGROUND
Adipose tissue is an important target for ethanol action. One important effect of ethanol is to reduce the secretion of adiponectin from adipocytes; this decrease is associated with lowered circulating adiponectin in rodent models of chronic ethanol feeding. Adiponectin is an insulin-sensitizing, anti-inflammatory adipokine; decreased adiponectin activity may contribute to tissue injury in response to chronic ethanol. Here, we investigated the role of cytochrome P450 2E1 (CYP2E1) and oxidative stress in the mechanism for impaired adiponectin secretion from adipocytes in response to ethanol.
METHODS
Male Wistar rats were fed a liquid diet containing ethanol as 36% of calories or pair-fed a control diet for 4 weeks. 3T3-L1 adipocyte cultures, expressing CYP2E1 or not, were exposed to ethanol or 4-hydroxynonenal (4-HNE).
RESULTS
Chronic ethanol feeding to rats suppressed the secretion of adiponectin from isolated epididymal adipocytes. Ethanol feeding induced the expression of CYP2E1 in adipocytes and increased markers of oxidative stress, including 4-HNE and protein carbonyls. Because adiponectin is posttranslationally processed in the endoplasmic reticulum and Golgi, we investigated the impact of ethanol on the redox status of high-density microsomes. Chronic ethanol decreased the ratio of reduced glutathione to oxidized glutathione (4.6:1, pair-fed; 2.9:1, ethanol-fed) in high-density microsomes isolated from rat epididymal adipose tissue. We next utilized the 3T3-L1 adipocyte-like cell model to interrogate the mechanisms for impaired adiponectin secretion. Culture of 3T3-L1 adipocytes overexpressing exogenous CYP2E1, but not those overexpressing antisense CYP2E1, with ethanol increased oxidative stress and impaired adiponectin secretion from intracellular pools. Consistent with a role of oxidative stress in impaired adiponectin secretion, challenge of 3T3-L1 adipocytes with 4-HNE also reduced adiponectin mRNA expression and secretion, without affecting intracellular adiponectin concentration.
CONCLUSIONS
These data demonstrate that CYP2E1-dependent reactive oxygen species production in response to ethanol disrupts adiponectin secretion from adipocytes.
背景
脂肪组织是乙醇作用的重要靶标。乙醇的一个重要作用是减少脂肪细胞分泌脂联素；这种减少与慢性乙醇喂养的啮齿动物模型中循环脂联素降低有关。脂联素是一种胰岛素增敏、抗炎的脂肪因子；脂联素活性降低可能导致组织损伤对慢性乙醇的反应。在这里，我们研究了细胞色素 P450 2E1 (CYP2E1) 和氧化应激在乙醇引起的脂肪细胞分泌脂联素受损机制中的作用。
方法
雄性 Wistar 大鼠喂食含乙醇作为 36%卡路里的液体饮食或配对喂食对照饮食 4 周。表达 CYP2E1 或不表达 CYP2E1 的 3T3-L1 脂肪细胞培养物暴露于乙醇或 4-羟基壬烯醛 (4-HNE)。
结果
慢性乙醇喂养大鼠抑制了从分离的附睾脂肪细胞分泌脂联素。乙醇喂养诱导脂肪细胞中 CYP2E1 的表达，并增加氧化应激标志物，包括 4-HNE 和蛋白质羰基。因为脂联素在内质网和高尔基体中进行翻译后加工，所以我们研究了乙醇对高密度微粒体氧化还原状态的影响。慢性乙醇降低了高密度微粒体中还原型谷胱甘肽与氧化型谷胱甘肽的比值（配对喂养：4.6:1；乙醇喂养：2.9:1）从大鼠附睾脂肪组织中分离出来。接下来，我们利用 3T3-L1 脂肪细胞样细胞模型来探究脂联素分泌受损的机制。用乙醇培养过表达外源性 CYP2E1 的 3T3-L1 脂肪细胞，但不是用反义 CYP2E1 过表达的细胞，会增加氧化应激并损害细胞内脂联素的分泌。与氧化应激在脂联素分泌受损中的作用一致，用 4-HNE 挑战 3T3-L1 脂肪细胞也会降低脂联素 mRNA 的表达和分泌，而不影响细胞内脂联素浓度。
结论
这些数据表明，乙醇引起的 CYP2E1 依赖性活性氧产生破坏了脂肪细胞分泌脂联素。
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