Abstract
Viral infections and antiviral responses have been linked to several metabolic diseases, including Reye's syndrome, which is aspirin-induced hepatotoxicity in the context of a viral infection. We identify an interferon regulatory factor 3 (IRF3)-dependent but type I interferon-independent pathway that strongly inhibits the expression of retinoid X receptor alpha (RXRalpha) and suppresses the induction of its downstream target genes, including those involved in hepatic detoxification. Activation of IRF3 by viral infection in vivo greatly enhances bile acid- and aspirin-induced hepatotoxicity. Our results provide a critical link between the innate immune response and host metabolism, identifying IRF3-mediated down-regulation of RXRalpha as a molecular mechanism for pathogen-associated metabolic diseases.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Down-Regulation / genetics
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Down-Regulation / immunology*
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Gene Expression Regulation, Viral / immunology*
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Hepatitis, Viral, Animal / genetics
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Hepatitis, Viral, Animal / immunology
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Hepatitis, Viral, Animal / metabolism*
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Interferon Regulatory Factor-3 / physiology*
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Mice
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Mice, Knockout
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Retinoid X Receptor alpha / antagonists & inhibitors*
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Retinoid X Receptor alpha / biosynthesis
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Retinoid X Receptor alpha / genetics
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Reye Syndrome / genetics
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Reye Syndrome / immunology
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Reye Syndrome / virology
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Rhabdoviridae Infections / genetics
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Rhabdoviridae Infections / immunology
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Rhabdoviridae Infections / metabolism
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Vesicular stomatitis Indiana virus / immunology
Substances
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Interferon Regulatory Factor-3
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Irf3 protein, mouse
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Retinoid X Receptor alpha