Control of Toxin and Obesity Induced Liver Fibrosis by B Cells

PROJECT 1

Control of Toxin and Obesity Induced Liver Fibrosis by B Cells

Project Summary/Abstract

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 lymphocytres, 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.

Publication

Shalapour S., Lin X.J., Bastian I.N., Brain J., Burt A.D., Aksenov A.A., Vrbanac A.F., Li W., Perkins A., Matsutani T., Zhong Z., Dhar D., Navas-Molina J.A., Xu J., Loomba R., Downes M., Yu R.T., Evans R.M., Dorrestein P.C., Knight R., Benner C., Anstee Q.M., Karin M. (2017). Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature. 551, 340-345. doi: 10.1038/nature24302.

PubMedID: 29144460

Chen S., Lu W., Yueh M.-F., Rettenmeier E., Liu M., Auwerx J., Yu R.T., Evans R.M., Wang K., Karin M., Tukey R.H. (2017) Intestinal NCoR1, a newly discovered regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia.  Proc. Nat. Acad. Sci. USA.114:E1432-E1440. doi: 10.1073/pnas.1700232114.

PubMedID: 28167773
PubMed Central ID: 

Moscat, J., Karin, M., Diaz-Meco, M.T. (2016) p62 in Cancer: Signaling Adaptor Beyond Autophagy. Cell. 167:606-609. doi:10.1016/j.cell.2016.09.030.

PubMedID: 27768885
PubMed Central ID: 

Duran, A., Hernandez, E.H, Reina-Campos, M, Castilla, E.A., Subramaniam, S., Raghunandan, S., Roberts, L.R., Kisseleva, T., Karin, M., Diaz-Meco, M.T., Moscat, J. (2016) p62/SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis and liver cancer. Cancer Cell. 30:595-609. doi: 10.1016/j.ccell.2016.09.004

PubMedID: 27728806
PubMed Central ID: 

Taniguchi, K., Yamachika, S., He, F., Karin, M. (2016) p62/SQSTM1- Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer. FEBS Lett. 590:2375-97.doi: 10.1002/1873-3468.12301

PubMedID: 27404485
PubMed Central ID: 

Lee, J.H., Cho, U.S., Karin, M. (2016) Sestrin regulation of TORC1: Is Sestrin a leucine sensor? Sci Signal. 9:re5. doi: 10.1126/scisignal.aaf2885

PubMedID: 27273098
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: 

Karin, M., Dhar, D. (2016) Liver Carcinogenesis: From Naughty Chemicals to Soothing Fat- and the Suprising Role of NRF2. Carcinogenesis. 37:541-6. doi: 10.1093/carcin/bgw060

PubMedID: 27207669
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. 2016 Feb 25;164(5):896-910. doi: 10.1016/j.cell.2015.12.057

PubMedID: 26919428
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Clevers H., Karin M. (2016) Reparative Inflammation Takes Charge of Tissue Regeneration. Nature. 529: 307-15. doi: 10.1038/nature17039.

PubMedID: 26791721
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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.

PubMedID: 26502405
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Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress. (2015) Antonucci, L., Fagman, J. B., Kim, J. Y., Todoric, J., Gukovsky, I., Mackey, M., Ellisman, M. H., Karin, M. Proc Natl Acad Sci U S A. 112(45), E6166-74.

PubMedID: 26512112
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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.

PubMedID: 26276631
PubMed Central ID: 

Parmigiani, A., Nourbakhsh, A., Ding, B., Wang, W., Kim, Y. C., Akopiants, K., Guan, K. L., Karin, M., Budanov, A. V. (2014) Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep. 9(4), 1281-91.

PubMedID: 25457612
PubMed Central ID: 

Yueh, M. F., Taniguchi, K., Chen, S., Evans, R. M., Hammock, B. D., Karin, M., Tukey, R. H. (2014) The commonly used antimicrobial additive triclosan is a liver tumor promoter. Proc Natl Acad Sci USA. 111(48), 17200-5.

PubMedID: 25404284
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.

PubMedID: 25132496
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.

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
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.

PubMedID: 24411937
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.

PubMedID: 24333183
PubMed Central ID: 

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. 

PubMedID: 24191041
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.

PubMedID: 24120137
PubMed Central ID: 

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.

PubMedID: 23341606
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.

PubMedID: 23271722
PubMed Central ID: 

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.

PubMedID: 22959272
PubMed Central ID: 

Lee, J. H., Budanov, A. V., Talukdar, S., Park, E. J., Park, H. L., Park, H. W., Bandyopadhyay, G., Li, N., Aghajan, M., Jang, I., Wolfe, A. M., Perkins, G. A., Ellisman, M. H., Bier, E., Scadeng, M., Foretz, M., Viollet, B., Olefsky, J., Karin, M. (2012) Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3. Cell Metab. 16(3), 311-21.

PubMedID: 22958918
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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.

PubMedID: 22705006

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.

PubMedID: 22698394
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Sun, B., Karin, M. (2012) Obesity, inflammation, and liver cancer. J Hepatol. 56(3), 704-13.

PubMedID: 22120206
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Fujiwara, R., Chen, S., Karin, M., Tukey, R.H. (2012) Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF-κB leads to hyperbilirubinemia. Gastroenterology. 142(1), 109-118.

PubMedID: 21983082
PubMed Central ID: 

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

PubMedID: 21962514
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
PubMed Central ID: 

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

PubMedID: 20878915
PubMed Central ID: 

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.

PubMedID: 20606249
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.

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.

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.

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.

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. 

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

PubMedID: 12202685

Main Contact Information

Dr. Michael Karin (American Cancer Society Research Professor, Pharmacology - UCSD)

Contact

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