High dietary fructose induces a hepatic stress response resulting in cholesterol and lipid dysregulation
High dietary fructose induces a hepatic stress response resulting in cholesterol and lipid dysregulation
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DOI：
10.1210/en.2003-1167
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发表时间：
2004-02-01
期刊：
影响因子：
4.8
通讯作者：
Azhar, S
中科院分区：
文献类型：
--
作者：
Kelley, GL;Allan, G;Azhar, S
高果糖喂养导致饮食诱导的脂质代谢改变和胰岛素敏感性降低，并导致肝脏丙酮酸脱氢酶和肝脏极低密度脂蛋白分泌的改变。炎症细胞因子还通过增加肝脏分泌和/或延迟极低密度脂蛋白的清除来诱导脂质代谢的显着变化，特别是血清甘油三酯的变化。本研究的目的是确定高果糖饮食中脂质失调的机制是否是由应激反应途径引起的。动物喂食高果糖饲料14天以建立高甘油三酯血症，然后在喂食饲料的同时接受脂氧合酶抑制剂治疗4天。在药物处理结束时，将动物分为两组，并用脂多糖或溶媒处理。在治疗前和治疗后采集血清样品，并在研究结束时收获肝组织。检测血清样品的代谢参数，并检测组织样品的代谢和应激途径反应。我们的研究结果表明，果糖喂养的大鼠在c-Jun N-末端激酶通路的变化与相应升高的激活蛋白-1活性，符合炎症反应。用脂氧合酶抑制剂治疗逆转了高脂血症，也减少了激活蛋白-1的激活，表明该模型中脂质失调的基础是由于肝脏中炎症途径的激活。
High-fructose feeding causes diet-induced alterations of lipid metabolism and decreased insulin sensitivity with alterations of hepatic pyruvate dehydrogenase and hepatic very low-density lipoprotein secretion. Inflammatory cytokines also induce dramatic changes in lipid metabolism, particularly in serum triglycerides via increased hepatic secretion and/or delayed clearance of very low-density lipoprotein. The aim of this study was to determine whether the mechanism of lipid dysregulation in the high-fructose diet is induced by stress response pathways. Animals were fed a high-fructose diet for 14 d to establish hypertriglyceridemia and then were treated with lipoxygenase inhibitors for 4 d concurrent with the diet. At the end of drug treatment, the animals were divided into two groups and treated with lipopolysaccharide or a vehicle. Serum samples were taken pretreatment and posttreatment, and liver tissue was harvested at the end of study. Serum samples were tested for metabolic parameters, and the tissue samples were tested for metabolic and stress pathway responses. Our results show that fructose-fed rats have changes in the c-Jun N-terminal kinase pathway with correspondingly elevated activator protein-1 activity, consistent with an inflammatory response. Treatment with lipoxygenase inhibitors reversed the hypertriglyceridemia and also reduced activator protein-1 activation, suggesting that the basis for lipid dysregulation in this model is due to activation of inflammatory pathways in the liver.