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  • Original Paper
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Retinoic acid inhibits hepatic Jun N-terminal kinase-dependent signaling pathway in ethanol-fed rats

Oncogene volume 21, pages 1539–1547 (2002)Cite this article

Abstract

Retinoic acid (RA) supplementation suppresses ethanol-enhanced hepatocyte hyperproliferation in rats; however, little is known about the mechanism(s). Here, we investigated whether RA affects the protein kinase signaling pathways in the liver tissues of rats fed with a high dose of ethanol for a prolonged period of time (6 months). Results show that there were greater levels of phosphorylated Jun N-terminal kinase (JNK) and phosphorylated c-Jun protein, but not total JNK protein, in livers of ethanol-fed rats vs those of controls. Moreover, ethanol feeding to rats increased the levels of phosphorylated mitogen-activated protein kinase kinase-4 (MKK-4) and decreased the levels of mitogen-activated kinase phosphatase-1 (MKP-1) in liver tissue. However, hepatic levels of phosphorylated-p38 protein and total-p38 protein were not altered by the ethanol treatment. In contrast, all-trans-RA supplementation at two doses in ethanol-fed rats greatly attenuated the ethanol-induced hepatic phosphorylation of MKK-4, phosphorylated-JNK and c-Jun proteins. The level of MKP-1 was increased in ethanol-fed rats supplemented with all-trans-RA. Further, ethanol-induced hepatocyte hyperproliferation, measured by immunostaining for proliferating cell nuclear antigen, were markedly decreased by all-trans-RA supplementation. Interestingly, hepatic apoptosis in the liver of ethanol-fed rats after 6 months of treatment decreased significantly. This decrease of hepatic apoptosis in ethanol-fed rats was prevented by all-trans-RA supplementation in a dose-dependent manner. The results from these studies indicate that restoration of RA homeostasis is critical for the regulation of JNK-dependent signaling pathway and apoptosis in the liver of ethanol-fed rats.

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Acknowledgements

We thank Dr Helen J Palmer for her helpful advice. This material is based upon work supported by grant R01CA49195 from the National Institute of Health, Bethesda, MD, USA, and by the US Department of Agriculture, under agreement No. 58-1950-9-001. Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the US Department of Agriculture.

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  1. Molecular Carcinogenesis Section, Gastrointestinal Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, 02111, Massachusetts, MA, USA

    Jayong Chung, Pollyanna RG Chavez, Robert M Russell & Xiang-Dong Wang

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  1. Jayong Chung
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  2. Pollyanna RG Chavez
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Correspondence to Xiang-Dong Wang.

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Chung, J., Chavez, P., Russell, R. et al. Retinoic acid inhibits hepatic Jun N-terminal kinase-dependent signaling pathway in ethanol-fed rats. Oncogene 21, 1539–1547 (2002). https://doi.org/10.1038/sj.onc.1205023

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