Effect of Underlying Liver Diseases on Fibrosis induced by Superfund Toxicants


​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.


PubMed Central ID: 

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

PubMedID: 28174735
PubMed Central ID: 

Koyama Y., Brenner D.A. (2017) Liver inflammation and fibrosis. J Clin Invest. 127:55-64. doi: 10.1172/JCI88881.

PubMedID: 28045404
PubMed Central ID: 

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.

PubMedID: 27911262
PubMed Central ID: 

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.

PubMedID: 27332862
PubMed Central ID: 

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.

PubMedID: 27211490
PubMed Central ID: 

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.

PubMedID: 27122117
PubMed Central ID: 

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.

PubMedID: 26922869
PubMed Central ID: 

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.

PubMedID: 26919428
PubMed Central ID: 

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.

PubMedID: 26909046
PubMed Central ID: 

Yang, Y. M., Seki, E. (2015) TNFα in liver fibrosis. Curr Pathobiol Rep. 3(4), 253-261.

PubMedID: 26726307
PubMed Central ID: 

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.

PubMedID: 26644586

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.

PubMedID: 26638191
PubMed Central ID: 

Yang, Y. M., Roh, Y. S., Seki, E. (2015) MafG, A Novel Target of FXR that Regulates Bile Acid Homeostasis. Gastroenterology. 149(7), 1981-3.

PubMedID: 26501563
PubMed Central ID: 

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.

PubMedID: 26447960
PubMed Central ID: 

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.

PubMedID: 26283048
PubMed Central ID: 

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.

PubMedID: 26222337
PubMed Central ID: 

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.

PubMedID: 26206573
PubMed Central ID: 

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

PubMedID: 25869468
PubMed Central ID: 

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.

PubMedID: 25850346
PubMed Central ID: 

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.

PubMedID: 25559344
PubMed Central ID: 

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.

PubMedID: 25466902

Roh, Y. S., Loomba, R., Seki, E. (2014) The TM6SF2 Variants, Novel Genetic Predictors for Nonalcoholic Steatohepatitis. Gastroenterology. pii: S0016-5085(14)01417-6.

PubMedID: 25451657

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.

PubMedID: 25218667
PubMed Central ID: 

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.

PubMedID: 25132496

Seki, E., Schwabe, R. F. (2014) Hepatic Inflammation and Fibrosis: Functional Links and Key Pathways. Hepatology. doi: 10.1002/hep.27332.

PubMedID: 25066777
PubMed Central ID: 

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.

PubMedID: 25043713
PubMed Central ID: 

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.

PubMedID: 24333183
PubMed Central ID: 

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.

PubMedID: 24983318
PubMed Central ID: 

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.

PubMedID: 24910242
Liang, S., Zhong, Z., Seki, E. (2014)  Novel fate-tracing strategies show that hepatic stellate cells mediate fibrosis in vivo. astroenterology. 146(7), 1823-5. 
PubMedID: 24768331
PubMed Central ID: 

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.

PubMedID: 24448807
PubMed Central ID: 

Roh, Y. S., Song, J., Seki, E. (2014) TAK1 regulates hepatic cell survival and carcinogenesis. J. Gastroenterol. 49(2),185-94.

PubMedID: 24443058
PubMed Central ID: 

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.

PubMedID: 24440671
PubMed Central ID: 

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.

PubMedID: 24411937
PubMed Central ID: 

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.

PubMedID: 24040957
PubMed Central ID: 

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.

PubMedID: 23996730
PubMed Central ID: 

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.

PubMedID: 24375615
PubMed Central ID: 

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.

PubMedID: 24368646
PubMed Central ID: 

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.

PubMedID: 24120137
PubMed Central ID: 

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.

PubMedID: 24019537
PubMed Central ID: 

Roh, Y. S., Seki, E. (2013) Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis. J Gastroenterol Hepatol. 1, 38-42.

PubMedID: 23855294
PubMed Central ID: 

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.

PubMedID: 23391818
PubMed Central ID: 

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.

PubMedID: 23271722
PubMed Central ID: 

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.

PubMedID: 22705006
PubMed Central ID: 

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.

PubMedID: 22698394

 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.

PubMedID: 22575885
PubMed Central ID: 

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.

PubMedID: 21173249

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


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