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Redundant roles for cJun-N-terminal kinase 1 and 2 in interleukin-1beta-mediated reduction and modification of murine hepatic nuclear retinoid X receptor alpha.

ABSTRACT: Retinoid X receptor alpha (RXRalpha), the heterodimeric partner for multiple nuclear receptors (NRs), was shown to be an essential target for inflammation-induced cJun-N-terminal kinase (JNK) signaling in vitro. This study aimed to explore the role of hepatic JNK signaling and its effects on nuclear RXRalpha levels downstream of interleukin-1beta (IL-1beta) in vivo.Effects of IL-1beta on hepatic NR-dependent gene expression, nuclear RXRalpha levels, and roles for individual JNK isoforms were studied in wild-type, Jnk1(-/-), and Jnk2(-/-) mice and in primary hepatocytes of each genotype.IL-1beta administration showed a time-dependent reduction in expression of the hepatic NR-dependent genes Ntcp, Cyp7a1, Cyp8b1, Abcg5, Mrp2, and Mrp3. IL-1beta treatment for 1h activated JNK and resulted in both post-translational modification and reduction of nuclear RXRalpha. In wild-type primary hepatocytes, IL-1beta modified and reduced nuclear RXRalpha levels time dependently, which was prevented by chemical inhibition of JNK as well as by inhibition of proteasomal degradation. Individual absence of either JNK1 or JNK2 did not significantly influence the reduction or modification of hepatic nuclear RXRalpha by IL-1beta both in vivo and in primary hepatocytes.Functional redundancy exists for JNK1 and JNK2 in IL-1beta-mediated alterations of hepatic nuclear RXRalpha levels, stressing the importance of this pathway in mediating the hepatic response to inflammation.

SUBMITTER: Kosters A

PROVIDER: S-EPMC2818213 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Redundant roles for cJun-N-terminal kinase 1 and 2 in interleukin-1beta-mediated reduction and modification of murine hepatic nuclear retinoid X receptor alpha.

Kosters Astrid A White Damara D DD Sun Hongdan H Thevananther Sundararajah S Karpen Saul J SJ

Journal of hepatology 20090820 5

<h4>Background/aims</h4>Retinoid X receptor alpha (RXRalpha), the heterodimeric partner for multiple nuclear receptors (NRs), was shown to be an essential target for inflammation-induced cJun-N-terminal kinase (JNK) signaling in vitro. This study aimed to explore the role of hepatic JNK signaling and its effects on nuclear RXRalpha levels downstream of interleukin-1beta (IL-1beta) in vivo.<h4>Methods</h4>Effects of IL-1beta on hepatic NR-dependent gene expression, nuclear RXRalpha levels, and ro ...[more]

PMID: 19767119

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Project description: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. 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-1beta, which suppresses PPARalpha expression and activity.

Dataset Information

Redundant roles for cJun-N-terminal kinase 1 and 2 in interleukin-1beta-mediated reduction and modification of murine hepatic nuclear retinoid X receptor alpha.

Publications

Redundant roles for cJun-N-terminal kinase 1 and 2 in interleukin-1beta-mediated reduction and modification of murine hepatic nuclear retinoid X receptor alpha.

Similar Datasets

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