C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis.
C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis.
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DOI：
10.2337/db09-1403
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发表时间：
2010-04
期刊：
影响因子：
7.7
通讯作者：
Ferrante AW Jr
中科院分区：
文献类型：
--
作者：
Obstfeld AE;Sugaru E;Thearle M;Francisco AM;Gayet C;Ginsberg HN;Ables EV;Ferrante AW Jr
肥胖会导致全身炎症，这与肥胖的许多临床后遗症的发展有关。肝脏炎症是肥胖性肝病的一个特征，我们先前的研究表明，肥胖小鼠肝脏脂肪变性减轻，缺乏调节髓系细胞募集的C-C趋化因子受体2(CCR2)。这表明，在肥胖的肝脏中，髓系细胞群体被招募到肝脏，并导致非酒精性脂肪性肝病。我们使用荧光激活细胞分选来测量遗传型和饮食型肥胖小鼠的肝白细胞数量。我们描述了增加和减少肥胖调节的肝白细胞CCR2表达群体的体内模型。最后，使用体外共培养系统，我们测量了这些细胞调节肝细胞脂肪代谢程序的能力。我们证明肥胖可激活肝细胞C-C趋化因子配体2(CCL2/MCP-1)的表达，导致肝脏中CCR2+髓系细胞的募集，从而促进肝骨病。这些细胞的数量与体重相关，在肥胖小鼠中，这些细胞的数量是肝脏中第二大免疫细胞。肝脏表达CCL2增加了他们的招募，并在饮食脂肪存在的情况下诱导肝骨病。这些细胞激活肝脏中与脂肪酸酯化和脂肪变性有关的基因转录。肥胖可诱导肝内髓系细胞重新聚集，从而促进肝细胞脂类的储存。这些发现表明，髓系细胞向代谢组织募集是肥胖的一个共同特征，并不局限于脂肪组织。
Obesity induces a program of systemic inflammation that is implicated in the development of many of its clinical sequelae. Hepatic inflammation is a feature of obesity-induced liver disease, and our previous studies demonstrated reduced hepatic steatosis in obese mice deficient in the C-C chemokine receptor 2 (CCR2) that regulates myeloid cell recruitment. This suggests that a myeloid cell population is recruited to the liver in obesity and contributes to nonalcoholic fatty liver disease. We used fluorescence-activated cell sorting to measure hepatic leukocyte populations in genetic and diet forms of murine obesity. We characterized in vivo models that increase and decrease an obesity-regulated CCR2-expressing population of hepatic leukocytes. Finally, using an in vitro co-culture system, we measured the ability of these cells to modulate a hepatocyte program of lipid metabolism. We demonstrate that obesity activates hepatocyte expression of C-C chemokine ligand 2 (CCL2/MCP-1) leading to hepatic recruitment of CCR2+ myeloid cells that promote hepatosteatosis. The quantity of these cells correlates with body mass and in obese mice represents the second largest immune cell population in the liver. Hepatic expression of CCL2 increases their recruitment and in the presence of dietary fat induces hepatosteatosis. These cells activate hepatic transcription of genes responsible for fatty acid esterification and steatosis. Obesity induces hepatic recruitment of a myeloid cell population that promotes hepatocyte lipid storage. These findings demonstrate that recruitment of myeloid cells to metabolic tissues is a common feature of obesity, not limited to adipose tissue.
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影响因子：
7.7
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
通讯作者：
Burcelin, Remy
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Matsusue, K;Haluzik, M;Gonzalez, FJ
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通讯作者：
Glimcher, Laurie H.
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4.8
作者：
Shimomura, I;Bashmakov, Y;Horton, JD
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Horton, JD