Control of Toxin and Obesity Induced Liver Fibrosis by B Cells

Research Project 1

Project Narative

Approximately one third of all industrial chemicals were found to induce fatty changes in liver, turned toxicant associated fatty liver disease (TAFLD) and toxicant associated steatoheapatits (TASH), whose pathology is similar to non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), metabolic disorder that greatly increase the risk of liver fibrosis/cirrhosis and liver cancer. Using mouse models of these liver diseases we will investigate the roles played by different populations of B lymphocytes in the development of toxicant and obesity induced liver fibrosis and cancer, diseases that disproportionally affect economically disadvantaged American Indians and Mexican Americans.

Summary of Project

Project 1 will generate and use mouse models for studying how exposure to hepatotoxic Superfund substances causes fatty liver disease and its different manifestations, including inflammation, fibrosis and cancer. It has become increasingly clear that exposure to many industrial and environmental toxicants can cause toxicant-associated fatty liver disease (TAFLD) and its more serious form, toxicant-associated steatohepatitis (TASH), whose pathological signs are strikingly similar to those of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic stateohepatits (NASH), respectively. As the pathogenic mechanisms underlying to TAFLD and TASH are poorly understood, we posit that better insight to toxicant-induced liver diseases can be gained from studying them along with NAFLD and NASH. Moreover, pre-existing NAFLD can increase the susceptibility of the liver to toxicant induced damage, further justifying the study of this metabolic condition that can progress to NASH or TASH and then to liver cirrhosis and cancer, diseases whose incidence is greater in economically disadvantaged Indian- and Mexican-American populations. During the past project period we obtained exciting and important preliminary results according to which the development and clinical progression of NASH and TASH are strongly modulated by two different populations of B lymphocytes, spleen-derived B2 B cells that promote fibrotic progression and IgA-producing plasmocytes that attenuate the onset of liver fibrosis, but favor the establishment of an immunosuppressive microenvironment permissive to the growth and progression of hepatocellular carcinoma (HCC). Correspondingly, the specific targeting of IgA+ plasmocytes results in immune rejection of established HCC. To better understand the role of these B populations in the development and progression of NASH and TASH and to generate a new therapeutic approach to the treatment of toxicant-and obesity-induced liver cancer we will: 1) Define the pathways responsible for B cell recruitment into toxicant-damaged steatotic livers; 2) Determine how TASH and NASH trigger IgA class switch recombination (CSR) in liver-infiltrating B cells; 3) Determine how IgA+ plasmocytes attenuate NASH- and TASH-associated liver fibrosis; 4) Determine the role of T cell subsets and microbiota in the development of NASH and TASH; 5) identify secreted metabolites that along with IgA can be used for non-invasive detection of liver fibrosis; 6) determine the role of IgA+ plasmocytes in NASH and TASH progression to HCC. Our ability to accomplish these goals and gain a much better understanding of the immune mechanisms that affect the pathogenesis of NASH and TASH will be greatly enhanced by our research cores and the close collaborative interactions with other research projects.


PubMed Central ID: 

Febbraio MA, Karin M. "Sweet death": Fructose as a metabolic toxin that targets the gut-liver axis. Cell Metab. 2021 Dec 7;33(12):2316-2328. doi: 10.1016/j.cmet.2021.09.004. Epub 2021 Oct 6. PMID: 34619076; PMCID: PMC8665123.

PubMedID: 34619076
PubMed Central ID: 

Xian H, Liu Y, Rundberg Nilsson A, Gatchalian R, Crother TR, Tourtellotte WG, Zhang Y, Aleman-Muench GR, Lewis G, Chen W, Kang S, Luevanos M, Trudler D, Lipton SA, Soroosh P, Teijaro J, de la Torre JC, Arditi M, Karin M, Sanchez-Lopez E. Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation. Immunity. 2021 Jul 13;54(7):1463-1477.e11. doi:10.1016/j.immuni.2021.05.004. Epub 2021 Jun 10. PMID: 34115964; PMCID: PMC8189765.

PubMedID: 34115964
PubMed Central ID: 

Kim JY, He F, Karin M. From Liver Fat to Cancer: Perils of the Western Diet. Cancers (Basel). 2021 Mar 4;13(5):1095. dio:10.3390/cancers13051095. PMID: 33806428; PMCID: PMC7961422.

PubMedID: 33806428
PubMed Central ID: 

Okuda K, Umemura A, Umemura S, Kataoka S, Taketani H, Seko Y, Nishikawa T, Yamaguchi K, Moriguchi M, Kanbara Y, Arbiser JL, Shima T, Okanoue T, Karin M, Itoh Y. Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor-MIG6 Axis. Cancers (Basel). 2021 Mar 25;13(7):1515. doi: 10.3390/cancers13071515. PMID: 33806040; PMCID: PMC8037653.

PubMedID: 33806040
PubMed Central ID: 

Yueh MF, He F, Chen C, Vu C, Tripathi A, Knight R, Karin M, Chen S, Tukey RH. Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):31259-31266. doi: 10.1073/pnas.2017129117. Epub 2020 Nov 23.

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Todoric J, Di Caro G, Reibe S, Henstridge DC, Green CR, Vrbanac A, Ceteci F, Conche C, McNulty R, Shalapour S, Taniguchi K, Meikle PJ, Watrous JD, Moranchel R, Najhawan M, Jain M, Liu X, Kisseleva T, Diaz-Meco MT, Moscat J, Knight R, Greten FR, Lau LF, Metallo CM, Febbraio MA, Karin M. Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat Metab. 2020 Oct;2(10):1034-1045. doi: 10.1038/s42255-020-0261-2. Epub 2020 Aug 24.

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He F, Antonucci L, Karin M. NRF2 as a regulator of cell metabolism and inflammation in cancer. Carcinogenesis. 2020 Jun 17;41(4):405-416. doi: 10.1093/carcin/bgaa039.

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He F, Antonucci L, Yamachika S, Zhang Z, Taniguchi K, Umemura A, Hatzivassiliou G, Roose-Girma M, Reina-Campos M, Molina AD, Diaz-Meco MT, Moscat J, Sun B, Karin M. (2020) NRF2 Activates Growth Factor Genes and Downstream AKT Signaling to Induce Mouse and Human Hepatomegaly. Journal of Hepatology, Accepted.
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Xu J, Ma HY, Liu X, Rosenthal S, Baglieri J, McCubbin R, Sun M, Koyama Y, Geoffroy CG, Saijo K, Shang L, Nishio T, Maricic I, Kreifeldt M, Kusumanchi P, Roberts A, Zheng B, Kumar V, Zengler K, Pizzo DP, Hosseini M, Contet C, Glass CK, Liangpunsakul S, Tsukamoto H, Gao B, Karin M, Brenner DA, Koob GF, Kisseleva T. Blockade of IL-17 signaling reverses alcohol-induced liver injury and excessive alcohol drinking in mice. JCI Insight. 2020 Feb 13;5(3):e131277. doi: 10.1172/jci.insight.131277.

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Zhao P, Sun X, Chaggan C, Liao Z, In Wong K, He F, Singh S, Loomba, R, Karin M, Witztum JL, Saltiel AR. (2020) An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis. Science. Feb 7; 367(6478):652-660.
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Ma HY, Yamamoto G, Xu J, Liu X, Karin D, Kim JY, Alexandrov LB, Koyama Y, Nishio T, Benner C, Heinz S, Rosenthal SB, Liang S, Sun M, Karin G, Zhao P, Brodt P, Mckillop IH, Quehenberger O, Dennis E, Saltiel A, Tsukamoto H, Gao B, Karin M, Brenner DA, Kisseleva T. (2019) IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease. J Hepatol. Dec 31.
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Febbraio, M.A., Reibe, S., Shalapour, S., Ooi, G.J., Watt, M.J., Karin, M.. (2019) Preclinical Models for Studying NASH-Driven HCC: How Useful Are They? Cell Metab. 29(1):18-26. doi: 10.1016/j.cmet.2018.10.012. Epub 2018 Nov 15. Review.

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Finkin, S., Yuan, D., Stein, I., Taniguchi, K., Weber, A., Unger, K., Browning, J. L., Goossens, N., Nakagawa, S., Gunasekaran, G., Schwartz, M. E., Kobayashi, M., Kumada, H., Berger, M., Pappo, O., Rajewsky, K., Hoshida, Y., Karin, M., Heikenwalder, M., Ben-Neriah, Y., Pikarsky, E. (2015) Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat Immunol. 16(12):1235-44. doi: 10.1038/ni.3290.

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Font-Burgada, J., Shalapour, S., Ramaswamy, S., Hsueh, B., Rossell, D., Umemura, A., Taniguchi, K., Nakagawa, H., Valasek, M. A., Ye, L, Kopp, J. L., Sander, M., Carter, H., Deisseroth, K., Verma, I. M., Karin, M. (2015) Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer. Cell. 162(4), 766-79. doi: 10.1016/j.cell.2015.07.026.

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Chen, S., Yueh, M. F., Bigo, C., Barbier, O., Wang, K., Karin, M., Nguyen, N., Tukey, R. H. (2013) Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11). Proc Natl Acad Sci USA. 110,19143-19148. doi: 10.1073/pnas.1319123110.

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Du, H., Sun, X., Guma, M., Luo, J., Ouyang, H., Zhang, X., Zeng, J., Quach, J., Nguyen, D. H., Shaw, P. X., Karin, M., Zhang, K. (2013) JNK inhibition reduces apoptosis and neovascularization in a murine model of age-related macular degeneration. Proc Natl Acad Sci USA. 110(6), 2377-82. doi: 10.1073/pnas.1221729110.

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Yu, G. Y., He, G., Li, C. Y., Tang, M., Grivennikov, S., Tsai, W. T., Wu, M. S., Hsu, C. W., Tsai, Y., Wang, L. H., Karin, M. (2012) Hepatic expression of HCV RNA-dependent RNA polymerase triggers innate immune signaling and cytokine production. Mol Cell. 48(2), 313-21. doi: 10.1016/j.molcel.2012.07.032.

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Holzer, R. G., Park, E. J., Li, N., Tran, H., Chen, M., Choi, C., Solinas, G., Karin, M. (2011) Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation. Cell. 147(1), 173-84. doi: 10.1016/j.cell.2011.08.034.

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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. doi: 10.1073/pnas.1017547108.

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Budanov, A. V., Lee, J. H., Karin, M. (2010) Stressin' sestrins take an aging fight. EMBO Mol Med. 2(10), 388-400. doi: 10.1002/emmm.201000097.

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Lee, J. H., Bodmer, R., Bier, E., Karin, M. (2010) Sestrins at the crossroad between stress and aging. Aging (Albany NY). 2(6), 369-74. doi: 10.18632/aging.100157

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PubMed Central ID: 

He, G., Yu, G. Y., Temkin, V., Ogata, H., Kuntzen, C., Sakurai, T., Sieghart, W., Peck-Radosavlijevic, M., Leffert, H. L., Karin, M. (2010) Hepatocyte IKKB/NF-KB inhibits tumor promotion and progression by preventing oxidative stress driven STAT3 activation. Cancer Cell. 17(3), 286-297. doi: 10.1016/j.ccr.2009.12.048.

PubMedID: 20227042
PubMed Central ID: 

Lee, J. H., Budanov, A. V., Park, E. J., Birse, R., Kim, T. E., Perkins, G. A., Ocorr, K., Ellisman, M. H., Bodmer, R., Bier, E., Karin, M. (2010) Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science. 327(5970),1223-8. doi: 10.1126/science.1182228.

PubMedID: 20203043
PubMed Central ID: 

Park, E., Lee, J., Yu, G. Y., He, G., Ali, S., Holzer, R., Osterreicher, C., Takahashi, H., Karin, M. (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 140, 197-208. doi: 10.1016/j.cell.2009.12.052.

PubMedID: 20141834
PubMed Central ID: 

Takahashi, H., Ogata, H., Nishigaki, R., Broide, D. H., Karin, M. (2010) Tobacco smoke promotes lung tumorigenesis by triggering IKKb and JNK1 dependent inflammation. Cancer Cell. 17, 89-97. doi: 10.1016/j.ccr.2009.12.008.

PubMedID: 20129250
PubMed Central ID: 

Koch, K. S., Maeda, S., He, G., Karin, M., Leffert, H. L. (2009) Targeted deletion of hepatocyte IKKβ; confers growth advantages. Biochem Biophys Res Commun. 380, 349-354. doi: 10.1016/j.bbrc.2009.01.085.

PubMedID: 19171122
PubMed Central ID: 

Budanov, A. V., Karin, M. (2008) p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell. 134(3), 451-60. doi: 10.1016/j.cell.2008.06.028.

PubMedID: 18692468
PubMed Central ID: 

Naugler, W. E., Karin, M. (2008) NF-KappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev. 18(1), 19-26. doi: 10.1016/j.gde.2008.01.020.

PubMedID: 18440219
PubMed Central ID: 

Sakurai, T., Maeda, S., Chang, L., Karin, M. (2006)  Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci USA. 103(28),10544-51. doi: 10.1073/pnas.0603499103

PubMedID: 16807293

Maeda, S., Kamata, H., Luo, J. L., Leffert, H., Karin, M. (2005)  IKKbeta; Couples Hepatocyte Cell Death to Cytokine-driven Compensatory Proliferation that Promotes Chemical Hepatocarcinogenesis. Cell. 121, 977-990. doi: 10.1016/j.cell.2005.04.014

PubMedID: 15989949

Kamata, H., Honda, S., Maeda, S., Chang, L., Hirata, H., Karin, M.  (2005) Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell. 120, 649-61. doi: 10.1016/j.cell.2004.12.041.

PubMedID: 15766528
PubMed Central ID: 

Valledor, A. F., Hsu, L. C., Ogawa, S., Sawka-Verhelle, D., Karin, M., Glass, C. K. (2004) Activation of liver X receptors and retinoid X receptors prevents bacterial-induced macrophage apoptosis. Proc Natl Acad Sci USA. 101(51), 17813-8. doi: 10.1073/pnas.0407749101

PubMedID: 15601766

Greten, F. R., Eckmann, L., Greten, T. F., Park, J. M., Li, Z. W., Egan, L. J., Kagnoff, M. F., Karin, M. (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 118(3), 285-96. doi: 10.1016/j.cell.2004.07.013

PubMedID: 15294155

Bonizzi, G., Karin, M. (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25(6), 280-8. doi: 10.1016/

PubMedID: 15145317

Galijatovic, A., Beaton, D., Nguyen, N., Chen, S., Bonzo, J., Johnson, R., Maeda, S., Karin, M., Guengerich, F. P., Tukey, R. H. (2004) The human CYP1A1 gene is regulated in a developmental and tissue-specific fashion in transgenic mice. J Biol Chem. 279(23), 23969-76. doi: 10.1074/jbc.M400973200

PubMedID: 15037607

Maeda, S., Chang, L., Li, Z. W., Luo, J. L., Leffert, H., Karin, M. (2003) IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity. 19(5), 725-37. doi: 10.1016/S1074-7613(03)00301-7.

PubMedID: 14614859

Li, Z. W., Omori, S. A., Labuda, T., Karin, M., Rickert, R. C. (2003) IKK beta is required for peripheral B cell survival and proliferation. J Immunol. 170(9), 4630-7. doi: 10.4049/jimmunol.170.9.4630.

PubMedID: 12707341

Chen, S., Nguyen, N., Tamura, K., Karin, M., Tukey, R. H. (2003) The role of the Ah receptor and p38 in benzo[a]pyrene-7,8-dihydrodiol and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide-induced apoptosis. J Biol Chem. 278(21), 19526-33. doi: 10.1074/jbc.M300780200.

PubMedID: 12637498

Park, J. M., Greten, F. R., Li, Z. W., Karin, M. (2002) Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science. 297(5589), 2048-51. doi: 10.1126/science.1073163

PubMedID: 12202685

Main Contact Information

Project Leader
  • Dr. Michael Karin
    American Cancer Society Research Professor/Distinguished Professor of Pharmacology, Department of Pharmacology, UCSD School of Medicine

Superfund Project Members
  • Juyoun Kim, Post-Doctoral Scholar
  • Anne Chang, Lab Manager

Also an Investigator on our:
Administrative Core


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