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.
Publications
Seki E. (2016) Acrolein, a New Villain in the Development of Alcoholic Liver Disease. Editorial.Cell Mol Gastroenterol Hepatol. 2:544-545. doi: 10.1016/j.jcmgh.2016.06.005
Koyama Y., Brenner D.A. (2017) Liver inflammation and fibrosis. J Clin Invest. 127:55-64. doi: 10.1172/JCI88881.
Park C.C., Nguyen P., Hernandez C., Bettencourt R., Ramirez K., Fortney L., Hooker J., Sy E., Savides M.T., Alquiraish M.H., Valasek M.A., Rizo E., Richards L., Brenner D., Sirlin C.B., Loomba R. (2017) Magnetic Resonance Elastography vs Transient Elastography in Detection of Fibrosis and Noninvasive Measurement of Steatosis in Patients With Biopsy-Proven Nonalcoholic Fatty Liver Disease. Gastroenterology. 152:598-607. doi: 10.1053/j.gastro.2016.10.026.
Koyama Y., Xu J., Liu X., Brenner D.A. (2016) New Developments on the Treatment of Liver Fibrosis. Dig Dis. 34:589-96. doi: 10.1159/000445269.
Umemura, A., He, F., Nakagawa, H., Yamachika, S., Taniguchi, K., Font-Burgada, J., Zhong, Z., Subramaniam, S., Raghunandan, S., Duran, A., Linares, J.F., Reina-Campos, M., Valasek, M.A., Seki, E., Yamaguchi, K., Koike, K., Itoh, Y., Diaz-Meco, M.T., Moscat, J., Karin, M. (2016) p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell. 29:935-48. doi: 10.1016/j.ccell.2016.04.006.
Hsin I.-F., Montano E., Seki E. (2016) Finding a New Role for NEMO: A Key Player in Preventing Hepatocyte Apoptosis and Liver Tumorigenesis by Inhibiting RIPK1. Hepatology Elsewhere. Hepatology. 64:295-7. doi: 10.1002/hep.28627.
Matsushita H., Yang Y.M., Pandol S.J., Seki E. (2016) Exosome Migration Inhibitory Factor as a Marker and Therapeutic Target for Pancreatic Cancer. Selected Summaries. Gastroenterology. 150:1033-5. doi: 10.1053/j.gastro.2016.02.051.
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. 164(5):896-910. doi: 10.1016/j.cell.2015.12.057.
Wang P., Koyama Y., Liu X., Xu J., Ma H.Y., Liang S., Kim I.H., Brenner D.A., Kisseleva T. (2016) Promising Therapy Candidates for Liver Fibrosis. Front Physiol. 7:47. doi: 10.3389/fphys.2016.00047.
Yang, Y. M., Seki, E. (2015) TNFα in liver fibrosis. Curr Pathobiol Rep. 3(4), 253-261.
Ding, N., Hah, N., Yu, R. T., Sherman, M. H., Benner, C., Leblanc, M., He, M., Liddle, C., Downes, M., Evans, R. M. (2015) BRD4 is a novel therapeutic target for liver fibrosis. Proc Natl Acad Sci U S A.112(51):15713-8. doi: 10.1073/pnas.1522163112.
Seki, E. (2015) HEDGEHOG signal in Hepatocytes mediates Macrophage Recruitment: A New Mechanism and Potential Therapeutic Target for Fatty Liver Disease. Hepatology. doi: 10.1002/hep.28381.
Brenner, D. A., Paik, Y. H., Schnabl, B. (2015) Role of Gut Microbiota in Liver Disease. J Clin Gastroenterol. 49 Suppl 1:S25-7. doi: 10.1097/MCG.0000000000000391.
Zhang, Z., Xie, Q., Jobe, T. O., Kau, A. R., Wang, C., Li, Y., Qiu, B., Wang, Q., Mendoza-Cózatl, D. G., Schroeder, J. I. (2015) Identification of AtOPT4 as a Plant Glutathione Transporter. Mol Plant. 9(3):481-484. doi: 10.1016/j.molp.2015.07.013.
Lan, T., Kisseleva, T., Brenner, D.A. (2015) Deficiency of NOX1 or NOX4 Prevents Liver Inflammation and Fibrosis in Mice through Inhibition of Hepatic Stellate Cell Activation. PLoS One. 10(7):e0129743. doi: 10.1371/journal.pone.0129743.
Koyama, Y., Brenner, D. A. (2015) New therapies for hepatic fibrosis. Clin Res Hepatol Gastroenterol. 39 Suppl 1, S75-9. doi: 10.1016/j.clinre.2015.06.011.
Seki, E., Brenner, D. A. (2015) Recent advancement of molecular mechanisms of liver fibrosis. J Hepatobiliary Pancreat Sci. 22(7):512-8. doi: 10.1002/jhbp.245
Kim, I. H., Kisseleva, T., Brenner, D. A. (2015) Aging and liver disease. Curr Opin Gastroenterol. 31(3):184-91. doi: 10.1097/MOG.0000000000000176.
Fang, S., Suh, J. M., Reilly, S. M., Yu, E., Osborn, O., Lackey, D., Yoshihara, E., Perino, A., Jacinto, S., Lukasheva, Y., Atkins, A. R., Khvat, A., Schnabl, B., Yu, R. T., Brenner, D. A., Coulter, S., Liddle, C., Schoonjans, K., Olefsky, J. M., Saltiel, A. R., Downes, M., Evans, R. M. (2015) Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 21(2):159-65. doi: 10.1038/nm.3760.
Mazagova, M., Wang, L., Anfora, A. T., Wissmueller, M., Lesley, S. A., Miyamoto, Y., Eckmann, L., Dhungana, S., Pathmasiri, W., Sumner, S., Westwater, C., Brenner, D. A., Schnabl, B. (2015) Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J. 29(3):1043-55. doi: 10.1096/fj.14-259515.
Roh, Y. S., Loomba, R., Seki, E. (2014) The TM6SF2 Variants, Novel Genetic Predictors for Nonalcoholic Steatohepatitis. Gastroenterology. pii: S0016-5085(14)01417-6.
Patel, N. S., Doycheva, I., Peterson, M. R., Hooker, J., Kisselva, T., Schnabl, B., Seki, E., Sirlin, C. B., Loomba, R. (2014) Effect of Weight Loss on Magnetic Resonance Imaging Estimation of Liver Fat and Volume in Patients With Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol. pii: S1542-3565(14)01316-0. doi: 10.1016/j.cgh.2014.08.039.
Nakagawa, H., Umemura, A., Taniguchi, K., Font-Burgada, J., Dhar, D., Ogata, H., Zhong, Z., Valasek, M. A., Seki, E., Hidalgo, J., Koike, K., Kaufman, R. J., Karin, M. (2014) ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell. 26(3), 331-43. doi: 10.1016/j.ccr.2014.07.001.
Seki, E., Schwabe, R. F. (2014) Hepatic Inflammation and Fibrosis: Functional Links and Key Pathways. Hepatology. doi: 10.1002/hep.27332.
Lopez-Sanchez, I., Dunkel, Y., Roh, Y. S., Mittal, Y., De Minicis, S., Muranyi, A., Singh, S., Shanmugam, K., Aroonsakool, N., Murray, F., Ho, S. B., Seki, E., Brenner, D. A., Ghosh, P. (2014) GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis. Nat Commun. 5:4451. doi: 10.1038/ncomms5451.
Moles, A., Murphy, L., Wilson, C. L., Chakraborty, J. B., Fox, C., Park, E. J., Mann, J., Oakley, F., Howarth, R., Brain, J., Masson, S., Karin, M., Seki, E., Mann, D. A. (2014) A TLR2/S100A9/CXCL-2 signaling network is necessary for neutrophil recruitment in acute and chronic liver injury in the mouse. J Hepatol. 60(4), 782-91. doi: 10.1016/j.jhep.2013.12.005.
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. doi: 10.1172/JCI74068.
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.
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. doi: 10.1074/jbc.M113.543769.
Roh, Y. S., Song, J., Seki, E. (2014) TAK1 regulates hepatic cell survival and carcinogenesis. J. Gastroenterol. 49(2),185-94.
Schnabl, B., Brenner, D. A. (2014) Interactions between the intestinal microbiome and liver diseases. Gastroenterology. 146(6):1513-24. doi: 10.1053/j.gastro.2014.01.020.
Dhar, D., Seki, E., Karin, M. (2014) NCOA5, IL-6, type 2 diabetes, and HCC: The deadly quartet. Cell Metab. 19(1), 6-7. doi: 10.1016/j.cmet.2013.12.010.
Paik, Y. H., Kim, J., Aoyama, T., De Minicis, S., Bataller, R., Brenner, D. A. (2014) Role of NADPH Oxidases in Liver Fibrosis. Antioxid Redox Signal. 20(17):2854-72. doi: 10.1089/ars.2013.5619.
Yang, L., Roh, Y. S., Song, J., Zhang, B., Liu, C., Loomba, R., Seki, E. (2014) Transforming growth factor beta signaling in hepatocytes participates in steatohepatitis through regulation of cell death and lipid metabolism in mice. Hepatology. 59(2), 483-95.
Roh, Y. S., Park, S., Kim, J. W., Lim, C. W., Seki, E., Kim, B. (2013) Toll-like receptor 7-mediated Type I Interferon signaling prevents cholestasis- and hepatotoxin-induced liver fibrosis. Hepatology. 10.1002/hep.26981.
Kudoh, K., Uchinami, H., Yoshioka, M., Seki, E., Yamamoto, Y. (2013) Nrf2 Activation Protects the Liver From Ischemia/Reperfusion Injury in Mice. Ann Surg. 260(1),118-27.
He, G., Dhar, D., Nakagawa, H., Font-Burgada, J., Ogata, H., Jiang, Y., Shalapour, S., Seki, E., Yost, S. E., Jepsen, K., Frazer, K. A., Harismendy, O., Hatziapostolou, M., Iliopoulos, D., Suetsugu, A., Hoffman, R. M., Tateishi, R., Koike, K., Karin, M. (2013) Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell. 155(2), 384-96. doi: 10.1016/j.cell.2013.09.031.
Madsen, D. H., Leonard, D., Masedunskas, A., Moyer, A., Jürgensen, H. J., Peters, D. E., Amornphimoltham, P., Selvaraj, A., Yamada, S. S., Brenner, D. A., Burgdorf, S., Engelholm, L. H., Behrendt, N., Holmbeck, K., Weigert, R., Bugge, T. H. (2013) M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway J Cell Biol. 202(6):951-66. doi: 10.1083/jcb.201301081.
Roh, Y. S., Seki, E. (2013) Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis. J Gastroenterol Hepatol. 1, 38-42.
Yang, L., Inokuchi, S., Roh, Y. S., Song, J., Loomba, R., Park, E. J., Seki, E. (2013) Transforming growth factor-β signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1. Gastroenterology. 144(5), 1042-1054.
Sakurai, T., Kudo, M., Umemura, A., He, G., Elsharkawy, A. M., Seki, E., Karin, M. (2013) p38α inhibits liver fibrogenesis and consequent hepatocarcinogenesis by curtailing accumulation of reactive oxygen species. Cancer Res. 73(1), 215-24. doi: 10.1158/0008-5472.CAN-12-1602.
Seki, E., Brenner, D. A., Karin, M. (2012) A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology. 143(2), 307-20. doi: 10.1053/j.gastro.2012.06.004.
Font-Burgada, J., Seki, E., Karin, M. (2012) CYLD and HCC: when being too sensitive to your dirty neighbors results in self-destruction. Cancer Cell. 21(6), 711-2. doi: 10.1016/j.ccr.2012.05.034.
Abe, Y., Uchinami, H., Kudoh, K., Nakagawa, Y., Ise, N., Watanabe, G., Sato, T., Seki, E., Yamamoto, Y. (2012) Liver epithelial cells proliferate under hypoxia and protect the liver from ischemic injury via expression of HIF-1 alpha target genes. Surgery. 152(5), 869-78.
Österreicher, C. H., Penz-Österreicher, M., Grivennikov, S. I., Guma, M., Koltsova, E. K., Datz, C., Sasik, R., Hardiman, G., Karin, M., Brenner, D. A. (2011) Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proc Natl Acad Sci USA. 108(1), 308-13.
Main Contact Information
Project Leaders
- Dr. David A. Brenner
- Dr. Ekihiro Seki
Superfund Related Project Members
- Karin Diggle, Lab Manager
- Jun Xu, Post-Doctoral Scholar
- Shuang Liang, Post-Doctoral Scholar
Resources (Brenner)
Dr. David Allen Brenner, M.D.
UCSD School of Medicine, Gastroenterology
UCSD Health Sciences, Center for Immunity, Infection, & Inflammation
Seki Laboratory, Cedars Sinai Medical Center
UCSD School of Medicine, Gastroenterology
Seki Laboratory, UCSD
Contact
UCSD Superfund Research Center
University of California, San Diego
Pharmacology Department
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722