Effect of Underlying Liver Diseases on Fibrosis induced by Superfund Toxicants

Summary

​Carbon tetrachloride (CCl4) is a Superfund toxicant (CERCLA Priority #47) that usually escapes into the environment as a gas, or it is sometimes found in water and soil. The liver is a primary target of the toxicity of CCl4. Exposure to high levels of CCl4 induces liver damage, inflammation and fibrosis. In healthy people, CCl4-induced liver injury and fibrosis can reverse when the exposure is discontinued. However, the response of people with underlying liver diseases, such as chronic hepatitis and fatty liver disease, may change, and their livers could be more susceptible to toxicants than healthy livers. Importantly, the health concerns, including chronic liver disease, are often raised regarding vulnerable communities near the Superfund sites. Therefore, the biological response for Superfund toxicants needs to be studied and early detection systems need to be developed for identifying these toxicants released into the environment and accumulating in organisms, including the human body. In this context, we will use mouse models with underlying liver diseases, such as Tak1∆HEPmice which have been developed by our laboratory, which mimic human chronic liver disease with liver fibrosis and cancer and mice fed high fat diet that induce obesity and fatty liver disease. Using experimental murine models of liver diseases, we will examine the effect of underlying liver diseases on long-term continuous exposure to CCl4 with respect to liver fibrosis and cancer. In addition to the evaluation of liver fibrosis by established methodology, we will create a sensitive new detection system for monitoring liver fibrosis using a new fluorescent protein and gene reporter system. This system will also evaluate the effect of another Superfund toxicant in the initiation of liver fibrosis. This project will provide new insights into the effect of environmental CCl4 exposure on people with underlying liver diseases, including chronic hepatitis and fatty liver. Underlying liver disease is a serious health concern in vulnerable communities, including tribal and low-income border communities that are the targets of our Superfund Research Center. We will share and disseminate our results through the Research Translation and Community Engagement Cores.

Publication

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Zhong, Z., Umemura, A., Sanchez-Lopez, E., Liang, S., Shalapour, S., Wong, J., He, F., Boassa, D., Perkins, G., Ali, S. R., McGeough, M. D., Ellisman, M. H., Seki, E., Gustafsson, A. B., Hoffman, H. M., Diaz-Meco, M. T., Moscat, J., Karin, M. (2016) NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell. 2016 Feb 25;164(5):896-910. doi: 10.1016/j.cell.2015.12.057

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Brenner, D. A., Paik, Y. H., Schnabl, B. (2015) Role of Gut Microbiota in Liver Disease. J Clin Gastroenterol. 49 Suppl 1:S25-7.

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Inokuchi-Shimizu, S., Park, E. J., Roh, Y. S., Yang, L., Zhang, B., Song, J., Liang, S., Pimienta, M., Taniguchi, K., Wu, X., Asahina, K., Lagakos, W., Mackey, M. R., Akira, S., Ellisman, M. H., Sears, D. D., Olefsky, J. M., Karin, M., Brenner, D. A., Seki, E. (2014) ETAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. J Clin Invest. 124(8), 3566-78.

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Umemura, A., Park, E. J., Taniguchi, K., Lee, J. H., Shalapour, S., Valasek, M. A., Aghajan, M., Nakagawa, H., Seki, E., Hall, M. N., Karin, M. (2014) Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition. Cell Metab. doi: 10.1016/j.cmet.2014.05.001.

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Liu, C., Chen, X., Yang, L., Kisseleva, T., Brenner, D. A., Seki, E. (2014) Transcriptional Repression of the Transforming Growth Factor β (TGF-β) Pseudoreceptor BMP and Activin Membrane-bound Inhibitor (BAMBI) by Nuclear Factor κB (NF-κB) p50 Enhances TGF-β Signaling in Hepatic Stellate Cells. J Biol Chem. 289(10), 7082-91.

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Main Contact Information

Ekihiro Seki, MD, Ph.D.
Cedars-Sinai Medical Center
8700 Beverly Blvd.
Los Angeles, CA 90048

P: 310-423-6605
F: 310-423-0653
E-Mail: Ekihiro.Seki@cshs.org

David Brenner, MD.
Professor of Medicine
Vice Chancellor, Health Sciences UC San Diego
Dean, UC San Diego School of Medicine
UC San Diego School of Medicine
UCSD Division of Gastroenterology
9500 Gilman Drive, La Jolla, CA 92093-0956
P: 858-657- 5284




Contact

UCSD Superfund Research Center
University of California, San Diego
Pharmacology Department
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722