Kupffer cells promote hepatic steatosis via interleukin-1β-dependent suppression of peroxisome proliferator-activated receptor α activity

内分泌学 库普弗电池 内科学 脂肪变性 过氧化物酶体增殖物激活受体 生物 川地68 脂肪肝 β氧化 受体 脂肪性肝炎 医学 免疫组织化学 新陈代谢 疾病
作者
Rinke Stienstra,Fredy Z. Saudale,Caroline Duval,Shohreh Keshtkar,J.E.M. Groener,Nico van Rooijen,Bart Staels,Sander Kersten,Michael Müller
出处
期刊:Hepatology [Wiley]
卷期号:51 (2): 511-522 被引量:415
标识
DOI:10.1002/hep.23337
摘要

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-1β 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 (PPARα), carnitine palmitoyltransferase 1A (Cpt1α), and fatty acid transport protein 2 (Fatp2). Treatment of mice with IL-1β decreased expression of PPARα and its target genes, which was confirmed in primary hepatocytes. Consistent with these data, IL-1β suppressed human and mouse PPARα promoter activity. Suppression of PPARα promoter activity was recapitulated by overexpression of nuclear factor κB (NF-κB) subunit p50 and p65, and was abolished upon deletion of putative NF-κB binding sites. Finally, IL-1β and NF-κB interfered with the ability of PPARα 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-1β, which suppresses PPARα expression and activity. (HEPATOLOGY 2010.)
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