Nutrigenomics Consortium, TI Food and Nutrition, Wageningen, The Netherlands.
Hepatology. 2010 Feb;51(2):511-22. doi: 10.1002/hep.23337.
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-1beta 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 (PPARalpha), carnitine palmitoyltransferase 1A (Cpt1alpha), and fatty acid transport protein 2 (Fatp2). Treatment of mice with IL-1beta decreased expression of PPARalpha and its target genes, which was confirmed in primary hepatocytes. Consistent with these data, IL-1beta suppressed human and mouse PPARalpha promoter activity. Suppression of PPARalpha promoter activity was recapitulated by overexpression of nuclear factor kappaB (NF-kappaB) subunit p50 and p65, and was abolished upon deletion of putative NF-kappaB binding sites. Finally, IL-1beta and NF-kappaB interfered with the ability of PPARalpha to activate gene transcription.
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-1beta, which suppresses PPARalpha expression and activity.
库普弗细胞(Kupffer cells)已被牵涉到各种肝脏疾病的发病机制中。然而，它们在包括脂肪肝疾病在内的肝脏代谢紊乱中的作用仍不清楚。本研究旨在确定库普弗细胞对肝甘油三酯储存的影响，并探讨可能涉及的机制。为此，用氯膦酸盐脂质体处理慢性高脂肪喂养导致肥胖和脂肪变性的 C57Bl/6 小鼠 1 周，氯膦酸盐脂质体可导致库普弗细胞耗竭。标志物基因 Cd68、F4/80 和 Clec4f 的表达缺失以及 Cd68 免疫染色的缺失证实了库普弗细胞几乎从肝脏中完全去除。此外，补体成分 C1、趋化因子（C-C 基序）配体 6（Ccl6）和细胞因子白细胞介素-15（IL-15）和白细胞介素-1β（IL-1β）的表达明显减少。重要的是，库普弗细胞耗竭显著降低了肝甘油三酯和葡糖脑苷脂水平，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）。用白细胞介素-1β（IL-1β）处理小鼠会降低 PPARα及其靶基因的表达，这在原代肝细胞中得到了证实。与这些数据一致，IL-1β抑制了人源和鼠源 PPARα 启动子活性。核因子 kappaB（NF-kappaB）亚基 p50 和 p65 的过表达可再现 PPARα 启动子活性的抑制，而潜在的 NF-kappaB 结合位点的缺失可消除这种抑制。最后，白细胞介素-1β（IL-1β）和 NF-kappaB 干扰了 PPARα激活基因转录的能力。
我们的数据表明，库普弗细胞和肝细胞之间在调节肝甘油三酯储存方面存在重要的交叉对话。库普弗细胞对肝脏甘油三酯的影响至少部分是由白细胞介素-1β（IL-1β）介导的，白细胞介素-1β（IL-1β）抑制 PPARα 的表达和活性。
