Cholesterol-induced hepatic inflammation does not contribute to the development of insulin resistance in male LDL receptor knockout mice
Cholesterol-induced hepatic inflammation does not contribute to the development of insulin resistance in male LDL receptor knockout mice
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DOI：
10.1016/j.atherosclerosis.2013.11.074
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发表时间：
2014-02-01
期刊：
影响因子：
5.3
通讯作者：
Koonen, Debby P. Y.
中科院分区：
文献类型：
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作者：
Funke, Anouk;Schreurs, Marijke;Koonen, Debby P. Y.
目的：一般认为肥胖的肝脏炎症与胰岛素抵抗的发病机制有关。最近的几项研究对这一观点提出了质疑，质疑这种联系的因果关系。这项研究的重点是Kupffer细胞介导的肝脏炎症，在没有肥胖和存在肥胖的情况下，它可能是胰岛素抵抗的驱动因素。方法：我们使用了低密度脂蛋白受体(Ldlr(-/-))缺陷的雄性小鼠，这些小鼠对胆固醇诱导的肝脏炎症敏感。用4种饲料，即饲料、高脂(HF)、HF-胆固醇(HFC；0.2%胆固醇)和不含胆固醇的HF(HFnC)饲喂2周和15周的小鼠，测定其全身和肝脏的胰岛素抵抗。测定血浆和肝脏生化指标，免疫组织化学和RT-PCR检测炎症反应。结果：2周时，除HFC饲料组小鼠肝脏炎症明显(p<；0.05)，胰岛素敏感性正常外，两组小鼠均未发现明显的代谢效应。在15周时，饲喂HFC、HFnC和HF饮食的小鼠的胰岛素水平、HOMA-IR和肝脏胰岛素抵抗显著高于饲喂食物的小鼠(p<；0.05)。无论肝脏炎症的程度如何(HFC>；HF，HFnC；P<；0.05)，喂食HFC的小鼠的胰岛素抵抗并不比喂食HFnC和HF的小鼠更差。结论：这些数据表明，胆固醇诱导的肝脏炎症不会促进雄性Ldlr(-/-)小鼠胰岛素抵抗的发展。这项研究表明，库普弗细胞驱动的肝脏炎症是肥胖患者代谢功能障碍的结果，而不是原因。(C)2013爱思唯尔爱尔兰有限公司。保留所有权利。
Objective: It is generally assumed that hepatic inflammation in obesity is linked to the pathogenesis of insulin resistance. Several recent studies have shed doubt on this view, which questions the causality of this association. This study focuses on Kupffer cell-mediated hepatic inflammation as a possible driver of insulin resistance in the absence and presence of obesity.Methods: We used male mice deficient for the low-density lipoprotein receptor (Ldlr(-/-)) and susceptible to cholesterol-induced hepatic inflammation. Whole body and hepatic insulin resistance was measured in mice fed 4 diets for 2 and 15 weeks, i.e., chow, high-fat (HF), HF-cholesterol (HFC; 0.2% cholesterol) and HF without cholesterol (HFnC). Biochemical parameters in plasma and liver were measured and inflammation was determined using immunohistochemistry and RT-PCR.Results: At 2 weeks, we did not find significant metabolic effects in either diet group, except for the mice fed a HFC diet which showed pronounced hepatic inflammation (p < 0.05) but normal insulin sensitivity. At 15 weeks, a significant increase in insulin levels, HOMA-IR, and hepatic insulin resistance was observed in mice fed a HFC, HFnC, and HF diet compared to chow-fed mice (p < 0.05). Regardless of the level of hepatic inflammation (HFC > HF, HFnC; p < 0.05) insulin resistance in mice fed HFC was no worse compared to mice on a HFnC and HF diet.Conclusion: These data show that cholesterol-induced hepatic inflammation does not contribute to the development of insulin resistance in male Ldlr(-/-) mice. This study suggests that Kupffer cell-driven hepatic inflammation is a consequence, not a cause, of metabolic dysfunction in obesity. (C) 2013 Elsevier Ireland Ltd. All rights reserved.