Journal
JOURNAL OF HEPATOLOGY
Volume 46, Issue 1, Pages 115-123Publisher
ELSEVIER
DOI: 10.1016/j.jhep.2006.09.008
Keywords
liver; inflammation; RXR; JNK; rosiglitazone; PPAR gamma; nuclear export
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Funding
- NIDDK NIH HHS [DK56338, DK56239, P30 DK056338, R01 DK056239] Funding Source: Medline
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK056239, P30DK056338] Funding Source: NIH RePORTER
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Background/Aims: A recently determined target of lipopolysaccharide (LPS) and cytokine signaling in liver is the central Type 11 nuclear receptor (NR) heterodimer partner, retinoid X receptor alpha (RXR alpha). We sought to determine if Rosiglitazone (Rosi), a peroxisome proliferator activated receptor gamma (PPAR gamma) agonist with anti-inflammatory properties, can attenuate LPS and cytokine-induced molecular suppression of RXR alpha-regulated genes. Methods: In vivo, mice were gavage-fed Rosi for 3 days, prior to intraperitoneal injection of LPS, followed by harvest of liver and serum. In vitro, HepG2 cells were treated with IL-1 beta, +/- short-term Rosi pretreatment. RNA was analyzed by quantitative RT-PCR, while nuclear and cytoplasmic proteins were analyzed by immunoblotting and gel shifts. Results: Rosi attenuated LPS-mediated suppression of RNA levels of several Type IINR-regulated genes, including bile acid transporters and the major drug metabolizing enzyme, Cyp3a11, without affecting cytokine expression, suggesting a novel, direct anti-inflammatory effect in hepatocytes. Rosi suppressed the inflammation-induced nuclear export of RXR alpha, in both LPS-injected mice and IL-1 beta-treated HepG2 cells, leading to maintenance of nuclear RXR alpha levels and heterodimer binding activity. Conclusions: Rosi directly attenuates the suppressive effects of inflammation-induced cell signaling on nuclear RXR alpha levels in liver. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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