Loss of Kupffer cells in diet-induced obesity is associated with increased hepatic steatosis, STAT3 signaling, and further decreases in insulin signaling.
Loss of Kupffer cells in diet-induced obesity is associated with increased hepatic steatosis, STAT3 signaling, and further decreases in insulin signaling.
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DOI：
10.1016/j.bbadis.2009.08.007
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发表时间：
2009-11
影响因子：
6.2
通讯作者：
Mooney, Robert A.
中科院分区：
文献类型：
--
作者：
Clementi, Alicia H.;Gaudy, Allison M.;van Rooijen, Nico;Pierce, Robert H.;Mooney, Robert A.
虽然脂肪组织相关的巨噬细胞有助于肥胖的慢性炎症和胰岛素抵抗的发展，但对肝库普弗细胞在这一环境中的作用知之甚少。在这里，我们研究了在饮食诱导的肥胖（DIO）和胰岛素抵抗小鼠模型中使用氯膦酸包封脂质体去除库普弗细胞消融的影响。尽管脂肪组织相关巨噬细胞的特征性扩增，但通过实时RT-PCR测量的DIO小鼠肝脏巨噬细胞标志物的表达保持不变。与瘦小鼠相比，DIO小鼠肝脏显示替代激活标记物的表达增加，但促炎细胞因子的表达不变。Kupffer细胞消融使瘦小鼠和DIO小鼠肝脏抗炎细胞因子IL-10 mRNA表达分别降低95%和84%。尽管瘦小鼠和DIO小鼠消融后肝脏IL-6基因表达降低，但肝脏STAT3磷酸化、Socs3和急性期蛋白mRNA表达增加。Kupffer细胞消融导致DIO小鼠肝脏甘油三酯积累增加，肝脏胰岛素受体自磷酸化和Akt激活减少30-40%。高脂肪喂养的IL-10敲除小鼠也表现出肝脏STAT3信号和肝脏甘油三酯积累增加，暗示IL-10的全身性损失。然而，胰岛素信号没有改变。总之，Kupffer细胞是肝脏IL-10表达的主要来源，其缺失与stat3依赖性信号和脂肪变性增加有关。然而，对于Kupffer细胞对DIO小鼠胰岛素受体信号传导的依赖性保护作用，似乎需要一个或多个额外的因素。
While adipose tissue-associated macrophages contribute to development of chronic inflammation and insulin resistance of obesity, little is known about the role of hepatic Kupffer cells in this environment. Here we address the impact of Kupffer cell ablation using clodronate-encapsulated liposome depletion in a diet-induced obese (DIO) and insulin resistant mouse model. Hepatic expression of macrophage markers measured by realtime RT-PCR remained unaltered in DIO mice despite characteristic expansion of adipose tissue-associated macrophages. DIO mouse livers displayed increased expression of alternative activation markers but unaltered proinflammatory cytokine expression when compared to lean mice. Kupffer cell ablation reduced hepatic anti-inflammatory cytokine IL-10 mRNA expression in lean and DIO mice by 95% and 84%, respectively. Despite decreased hepatic IL-6 gene expression after ablation in lean and DIO mice, hepatic STAT3 phosphorylation, Socs3 and acute phase protein mRNA expression increased. Kupffer cell ablation in DIO mice resulted in additional hepatic triglyceride accumulation and a 30-40% reduction in hepatic insulin receptor autophosphorylation and Akt activation. Implicating systemic loss of IL-10, high-fat-fed IL-10 knockout mice also displayed increased hepatic STAT3 signaling and hepatic triglyceride accumulation. Insulin signaling was not altered, however. In conclusion, Kupffer cells are a major source of hepatic IL-10 expression, the loss of which is associated with increased STAT3-dependent signaling and steatosis. One or more additional factors appear to be required, however, for the Kupffer cell-dependent protective effect on insulin receptor signaling in DIO mice.
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影响因子：
4.8
作者：
den Boer, Marion A. M.;Voshol, Peter J.;Romijn, Johannes A.
通讯作者：
Romijn, Johannes A.
影响因子：
15.9
作者：
Burant, CF;Sreenan, S;Graves, RA
通讯作者：
Graves, RA
影响因子：
7.7
作者：
Boden, G;She, PX;Ruderman, N
通讯作者：
Ruderman, N
影响因子：
64.8
作者：
Houstis, N;Rosen, ED;Lander, ES
通讯作者：
Lander, ES
肿瘤坏死因子-α的脂肪表达--在与肥胖相关的胰岛素抵抗中的直接作用
影响因子：
56.9
作者：
HOTAMISLIGIL, GS;SHARGILL, NS;SPIEGELMAN, BM
通讯作者：
SPIEGELMAN, BM