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

Stienstra, Rinke, Saudale, Fredy, Duval, Caroline, Keshtkar, Shohreh, Groener, Johanna E. M., van Rooijen, Nico, Staels, Bart, Kersten, Sander and Müller, Michael (2010) Kupffer cells promote hepatic steatosis via interleukin-1β-dependent suppression of peroxisome proliferator-activated receptor α activity. Hepatology, 51 (2). pp. 511-522. ISSN 0270-9139

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Abstract

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.Tothat 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)andIL-1βweremarkedlyreduced. 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-1βdecreased expression of PPARαand its target genes, which was confirmed in primary hepatocytes. Consistent with these data, IL-1βsuppressed human and mouse PPARαpromoter activity. Suppression of PPARαpromoter activity was recapitulated by overexpression of nuclear factor κB (NF-κB) subunit p50 and p65, and was abolished upon deletion of putative NF-κBbinding sites. Finally, IL-1βand NF-κB interfered with the ability of PPARαto 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.

Item Type: Article
Uncontrolled Keywords: animals,fatty liver,interleukin-1beta,kupffer cells,male,mice,mice, inbred c57bl,ppar alpha
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: Pure Connector
Date Deposited: 18 Dec 2013 11:32
Last Modified: 14 Sep 2020 07:02
URI: https://ueaeprints.uea.ac.uk/id/eprint/47049
DOI: 10.1002/hep.23337

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