Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance.
Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance.
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DOI：
10.2337/db09-0016
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发表时间：
2010-02
期刊：
影响因子：
7.7
通讯作者：
O'Doherty RM
中科院分区：
文献类型：
--
作者：
Huang W;Metlakunta A;Dedousis N;Zhang P;Sipula I;Dube JJ;Scott DK;O'Doherty RM
先天免疫系统活性的增加与肥胖和2型糖尿病相关的血脂异常和胰岛素抵抗的发病机制有关。在这项研究中，我们解决了枯否细胞（肝脏特异性巨噬细胞，KCs）在这些代谢异常中的潜在作用。通过给予氯化钆耗尽大鼠的KC，之后所有动物暴露于2周的高脂肪或高蔗糖饮食。随后，评估这些干预措施对肝脏胰岛素抵抗和脂肪变性发展的影响。在进一步的研究中，M1极化KCs对肝细胞脂质代谢和胰岛素敏感性的影响被解决。正如预期的那样，高脂肪或高糖饮食诱导脂肪变性和肝脏胰岛素抵抗。然而，当肝脏耗尽KCs时，这些代谢异常被阻止。在体外，KCs通过增加肝细胞甘油三酯积累和脂肪酸酯化，降低脂肪酸氧化和胰岛素反应性来再现饮食的体内效应。为了解决KC作用的机制，我们使用中和抗体抑制一组细胞因子。仅肿瘤坏死因子-α（TNFα）中和抗体可减弱KC诱导的肝细胞脂肪酸氧化、甘油三酯蓄积和胰岛素反应性改变。重要的是，在体内和体外分离的M1极化KC中，KC TNFα水平通过饮食增加。这些数据证明了肝脏巨噬细胞在饮食诱导的肝脏脂质代谢和胰岛素敏感性改变中的作用，并表明这些细胞在肥胖/2型糖尿病代谢异常的病因学中的作用。
Increased activity of the innate immune system has been implicated in the pathogenesis of the dyslipidemia and insulin resistance associated with obesity and type 2 diabetes. In this study, we addressed the potential role of Kupffer cells (liver-specific macrophages, KCs) in these metabolic abnormalities. Rats were depleted of KCs by administration of gadolinium chloride, after which all animals were exposed to a 2-week high-fat or high-sucrose diet. Subsequently, the effects of these interventions on the development of hepatic insulin resistance and steatosis were assessed. In further studies, the effects of M1-polarized KCs on hepatocyte lipid metabolism and insulin sensitivity were addressed. As expected, a high-fat or high-sucrose diet induced steatosis and hepatic insulin resistance. However, these metabolic abnormalities were prevented when liver was depleted of KCs. In vitro, KCs recapitulated the in vivo effects of diet by increasing hepatocyte triglyceride accumulation and fatty acid esterification, and decreasing fatty acid oxidation and insulin responsiveness. To address the mechanisms(s) of KC action, we inhibited a panel of cytokines using neutralizing antibodies. Only neutralizing antibodies against tumor necrosis factor-α (TNFα) attenuated KC-induced alterations in hepatocyte fatty acid oxidation, triglyceride accumulation, and insulin responsiveness. Importantly, KC TNFα levels were increased by diet in vivo and in isolated M1-polarized KCs in vitro. These data demonstrate a role for liver macrophages in diet-induced alterations in hepatic lipid metabolism and insulin sensitivity, and suggest a role for these cells in the etiology of the metabolic abnormalities of obesity/type 2 diabetes.
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影响因子：
82.9
作者：
Arkan, MC;Hevener, AL;Karin, M
通讯作者：
Karin, M
影响因子：
7.7
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
通讯作者：
Burcelin, Remy
DOI：
10.1152/ajpregu.2001.281.5.r1380
发表时间：
2001-11-01
影响因子：
2.8
作者：
Commerford, SR;Bizeau, ME;Pagliassotti, MJ
通讯作者：
Pagliassotti, MJ
DOI：
10.1073/pnas.0504978102
发表时间：
2005-08-02
影响因子：
11.1
作者：
Ley, RE;Bäckhed, F;Gordon, JI
通讯作者：
Gordon, JI
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