Kupffer Cells Promote Hepatic Steatosis Via Interleukin-1β-Dependent Suppression of Peroxisome Proliferator-Activated Receptor α Activity
Kupffer Cells Promote Hepatic Steatosis Via Interleukin-1β-Dependent Suppression of Peroxisome Proliferator-Activated Receptor α Activity
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DOI：
10.1002/hep.23337
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发表时间：
2010-02-01
期刊：
影响因子：
13.5
通讯作者：
Mueller, Michael
中科院分区：
文献类型：
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作者：
Stienstra, Rinke;Saudale, Fredy;Mueller, Michael
库普弗细胞与多种肝脏疾病的发病机制有关。然而，它们与肝脏代谢紊乱（包括脂肪肝疾病）的关系仍不清楚。本研究旨在确定库普弗细胞对肝脏甘油三酯储存的影响，并探讨其中可能的机制。为此，用氯膦酸盐脂质体治疗因长期高脂肪喂养而导致肥胖和脂肪变性的 C57Bl/6 小鼠 1 周，从而消除库普弗细胞。标记基因 Cd68、F4/80 和 Clec4f 表达的丧失以及 Cd68 免疫染色的丧失证实库普弗细胞几乎完全从肝脏中去除。此外，补体成分 C1、趋化因子（C-C 基序）配体 6 (Ccl6) 以及细胞因子白细胞介素 15 (IL-15) 和 IL-1 β 的表达显着降低。重要的是，库普弗细胞耗竭显着降低了肝脏甘油三酯和葡萄糖神经酰胺水平，同时参与脂肪酸氧化的基因表达增加，包括过氧化物酶体增殖物激活受体α（PPARα）、肉碱棕榈酰转移酶1A（Cpt1α）和脂肪酸转运蛋白2（Fatp2）。用IL-1β治疗小鼠可降低PPARα及其靶基因的表达，这一点在原代肝细胞中得到证实。与这些数据一致，IL-1β 抑制人和小鼠 PPARα 启动子活性。 PPAR α 启动子活性的抑制通过核因子 kappa B (NF-kappa B) 亚基 p50 和 p65 的过表达来重现，并且在删除假定的 NF-kappa B 结合位点后被消除。最后，IL-1β 和 NF-κB 干扰 PPARα 激活基因转录的能力。结论：我们的数据表明库普弗细胞和肝细胞之间在肝脏甘油三酯储存调节中存在重要的相互作用。库普弗细胞对肝脏甘油三酯的影响至少部分是由 IL-1 β 介导的，IL-1 β 抑制 PPAR α 的表达和活性。 （肝病学 2010；51：511-522。）
Kupffer cells have been implicated in the pathogenesis of various liver diseases. However, their involvement in metabolic disorders of the liver, including fatty liver disease, remains unclear. The present study sought to determine the impact of Kupffer cells on hepatic triglyceride storage and to explore the possible mechanisms involved. To that end, C57Bl/6 mice rendered obese and steatotic by chronic high-fat feeding were treated for 1 week with clodronate liposomes, which cause depletion of Kupffer cells. Loss of expression of marker genes Cd68, F4/80, and Clec4f, and loss of Cd68 immunostaining verified almost complete removal of Kupffer cells from the liver. Also, expression of complement components C1, the chemokine (C-C motif) ligand 6 (Ccl6), and cytokines interleukin-15 (IL-15) and IL-1 beta were markedly reduced. Importantly, Kupffer cell depletion significantly decreased liver triglyceride and glucosylceramide levels concurrent with increased expression of genes involved in fatty acid oxidation including peroxisome proliferator-activated receptor alpha (PPAR alpha), carnitine palmitoyltransferase 1A (Cpt1 alpha), and fatty acid transport protein 2 (Fatp2). Treatment of mice with IL-1 beta decreased expression of PPAR alpha and its target genes, which was confirmed in primary hepatocytes. Consistent with these data, IL-1 beta suppressed human and mouse PPAR alpha promoter activity. Suppression of PPAR alpha promoter activity was recapitulated by overexpression of nuclear factor kappa B (NF-kappa B) subunit p50 and p65, and was abolished upon deletion of putative NF-kappa B binding sites. Finally, IL-1 beta and NF-kappa B interfered with the ability of PPAR alpha to activate gene transcription. Conclusion: Our data point toward important cross-talk between Kupffer cells and hepatocytes in the regulation of hepatic triglyceride storage. The effect of Kupffer cells on liver triglycerides are at least partially mediated by IL-1 beta, which suppresses PPAR alpha expression and activity. (HEPATOLOGY 2010;51:511-522.)