Laboratory of Liver Diseases

Contact Information

  • Office: 301.443.3998
  • Fax: 301 480.0257

Overview of the Lab

The mission of the Laboratory of Liver Diseases is to investigate the immunological aspects and molecular pathogenesis of alcoholic and nonalcoholic fatty liver diseases, and to explore novel therapeutic targets for the treatment of these disorders. 

Research Projects

Alcoholic liver disease (ALD)

ALD is a major cause of chronic liver disease, leading to cirrhosis and liver cancer. The latest report from our institute (NIAAA) shows that cirrhosis is the 12th leading cause of deaths in the US with a total of 29,925 deaths in 2007, of which 48% were alcohol-related. The spectrum of ALD includes steatosis, alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. At present, there are no small animal models available that reproduce the full spectrum of human ALD. Thus, our laboratory has been actively using liver injury models (induced by ethanol and/or other insults) and collaborating with several clinical investigators to conduct translational research on the pathogenesis and novel therapeutic targets for ALD with focusing on the following projects.

  1. Chronic-plus-binge ethanol feeding model: Recently, we have developed a chronic-plus-binge ethanol feeding model in mice, which is similar to the drinking pat­tern of many alcoholic hepatitis patients. Such chronic-plus-binge ethanol feeding synergistically induced steatosis, liver injury and neutrophil infiltration in mice, which has been useful for the study of early ALD and inflammation. We will continue to characterize and use this model to investigate the underlying mechanisms and explore novel therapeutic targets of ALD.
  2. Inflammation in ALD: Frank Burr Mallory's landmark observation in 1911 on the histopathology of alcoholic liver disease (ALD) was the first identification of a link between inflammation and ALD. However, the role of inflammation in the pathogenesis of ALD still remains largely obscure. Our laboratory has been actively investigating the role of innate immunity in the pathogenesis of ALD.
  3. ALDH2 deficiency in ALD: Aldehyde dehydrogenase 2 (ALDH2) is the major enzyme that metabolizes acetaldehyde produced from alcohol metabolism. Approximately 40~50% of East Asians carry an inactive ALDH2 gene and exhibit acetaldehyde accumulation after alcohol consumption. However, the role of ALDH2 deficiency in pathogenesis of ALD remains poorly understood. We are interested in investigating the effects of ALDH2 deficiency on liver inflammation, fibrosis, and cancer in the pathogenesis of ALD.
  4. Novel therapeutic targets of ALD: Despite the profound economic and health impact of ALD, little progress has been made in the management of patients with severe forms of ALD and there are no FDA-approved therapies for ALD. Our laboratory has been comprehensively investigating hepatoprotective cytokines in ALD and involving in translating these findings into new therapies for ALD. 

Nonalcoholic fatty liver disease (NAFLD)

NAFLD is another major cause of chronic liver disease worldwide, which is often associated with obesity and diabetes. The spectrum of NAFLD includes simple fatty liver, steatohepatitis (inflammation), fibrosis, and liver cancer. It is believed that inflammation is a key factor driving the progression of NAFLD. We are interested in investigating the role of inflammation in the pathogenesis of NAFLD-associated liver injury, fibrosis, and cancer, and exploring therapeutic targets for the treatment of NAFLD. 

Innate Immunity in the liver

Blood circulating from the intestines to the liver is rich in bacterial products, environmental toxins, and food antigens. To effectively and quickly defend against potentially toxic agents without launching harmful immune responses, the liver relies on its strong innate immune system. This comprises enrichment of innate immune cells (such as macrophages, natural killer, natural killer T, and gammadelta T cells) and removal of waste molecules and immunologic elimination of microorganisms by liver endothelial cells and Kupffer cells. In addition, the liver also plays an important role in controlling systemic innate immunity through the biosynthesis of numerous soluble pathogen-recognition receptors and complement components. Our lab has been actively characterizing hepatic innate immunity and exploring its functions in liver injury, regeneration, fibrosis, and cancer.

Lab Members

Selected Publications

Selected Original Articles (over 200): 

 

  1. He, Y., Rodrigues, R., Wang, X., Seo, W., Ma, J., Hwang, S., Trojnár, E., Mátyás, C., Ren, R., Feng, D., Pacher, P., Kunos, G., and Gao, B.: Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223-enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis. Journal of Clinical Investigation 2020 Dec 10:141513. doi: 10.1172/JCI141513
  2. Zhang, Q., Ma, C., Duan, Y., Heinrich, B., Rosato, U., Diggs, LP., Ma, L., Roy, S., Fu, Q., Brown, ZJ., Wabitsch, S., Thovarai, V., Fu, J., Feng, D., Ruf, B., Cui, LL., Subramanyam, V., Frank, KM., Wang, S., Kleiner, DE., Ritz, T., Rupp, C., Gao, B., Longerich. T., Kroemer, A., Wang, XW., Ruchirawat, M., Korangy, F., Schnabl, B., Trinchieri, G., Greten, TF.:  Gut microbiome directs hepatocytes to recruit MDSC and promote cholangiocarcinoma. Cancer Discovery 2020 Dec 15:CD-20-0304. doi: 10.1158/2159-8290
  3. Hwang, S., He, Y., Xiang, X., Seo, W., Kim, S., Ma, J., Ren, T., Park, S., Zhou, Z., Feng, D., Kunos, G., Gao, B.: Interleukin-22 ameliorates neutrophil-driven nonalcoholic steatohepatitis through multiple targets. Hepatology 2020; 72(2):412-429 
  4. Xiang, X., Feng, D., Hwang, S., Ren, T., Matyas, C., Wang, X., Mo, R., Shang, D., Trojnar, E., He, Y., Seo, W., Shah, V., Pacher, P., Xie, Q., Gao, B.: Interleukin-22 ameliorates acute-on-chronic liver failure by reprogramming of impaired regeneration pathways. Journal of Hepatology 2020; 72,736-745  
  5. Ma, J., Cao, H., Rodrigues, R., Xu, M., Ren, T., He, Y., Hwang, S., Feng, D., Ren, R., Yang, P., Liangpunsakul, S., Sun, J., Gao, B.: Chronic-plus-binge alcohol intake induces proinflammatory mtDNA-enriched extracellular vesicles and steatohepatitis via the ASK-1 and p38MAPKalpha-dependent pathway. Journal of Clinical Investigation Insight  2020;5(14):136496
  6. Xu, J., Ma, H., Liu, X., Rosenthal, S., Baglieri, J., McCubbin, R., Sun, M., Koyama, Y., Geoffroy, C., Saijo, K.,  Shang, L., Nishio, T.,  Maricic, I., Kreifeldt, M., Kusumanchi, P., Roberts, A., Zheng, B., Kumar, V., Zengler, K., Pizzo, D., Hosseini, M., Contet, C., Glass, C., Liangpunsakul, S., Tsukamoto, H., Gao, B., Karin, M., Brenner, D., Koob, G., Kisseleva, T.: Blockade of lL17 signaling reverses alcohol-induced liver and brain injury, and excessive alcohol drinking in mice. Journal of Clinical Investigation Insight 2020; 5(3):e131277
  7. Liu, F., Dai, S., Feng, D., Qin, Z., Peng, X., Sakamuri, S., Huang, L., Cheng, M., Mohammad, K., Qu, P., Chen, Y., Zhao, C., Zhu, F., Liang, S., Aktas, B., Yang, X., Wang, H., Katakam, P., Busija, D., Fischer, T., Datta, P., Rappaport, J., Gao, B., and Qin, X: Characterization of renal macrophage (RM) fate, dynamics, and niches: embryonic RMs are more sensitive to immune challenges than bone marrow-derived RMs. Nature Communication 2020; 8;11(1):2280. doi: 10.1038/s41467-020-16158-z
  8. Arab, J., Sehrawat, T., Simonetto, D., Verma, V., Feng, D., Tang, T., Dreyer, K., Yan, X., Daley, W., Sanyal, A., Chalasani, N., Radaeva, S., Yang, L., Vargas, H., Gao, B., Gores, G., Malhi, H., Kamath, P., Shah, V.: An open label, cohort dose escalation study to assess the safety and efficacy of IL-22 agonist F-652 in patients with alcoholic hepatitis. Hepatology 2020;72(2):441-453
  9. Ma, H., Yamamoto, G., Xu, J., Liu, X., Karin, D., Kim, J., Alexandrov, L., Koyama, Y., Nishio, T., Benner, C., Heinz, S., Rosenthal, S., Liang, S., Sun, M., Karin, G., Zhao, P., Brodt, P., Mckillop, I., Quehenberger, O., Dennis, E., Saltiel, A., Tsukamoto, H., Gao, B., Karin, M., Brenner, D., Kisseleva, T.: IL-17 signaling in steatotic hepatocytes and macrophages promotes alcoholic liver disease-induced hepatocellular carcinoma. Journal of Hepatology 2020;72:946-959
  10. Bernier, M., Mitchell, S., Wahl, D., Diaz, A., Singh, A., Seo, W., Wang, Y., Ali, A., Kaiser, T., Price, N., Aon, M., Kim, E., Petr, M., Cai, H., Warren, A., Germanio, C., Francesco, A., Fishbein, K., Guiterrez, V., Harney, D., Koay, Y., Mach, J., Enamorado, I., Pulpitel, T., Wang, Y., Zhang, J., Zhang, L., Spencer, R., Becker, K., Egan, J., Lakatta, E., O’Sullivan, J., Larance, M., LeCouteur, D., Cogger, V., Gao, B., Fernandez-Hernando, C., Cuervo, A., and de Cabo, R.: Disulfiram treatment normalizes body weight in obese mice. Cell Metabolism 2020;32:203-214
  11. Hwang, S., Wang, X., Rodrigues, R., Ma, J., He, Y., Seo, W., Park, S., Kim, S., Feng, D., and Gao, B.: Protective and detrimental roles of p38alpha MAPK in different stages of nonalcoholic fatty liver disease. Hepatology 2020;72(3):873-891
  12. Kim, W., Cho, Y., Wang, X., Park, O., Ma, X., Kim, H., Gan, W., Jho, E., Cha, B., Jeung, W., Zhang, L., Gao, B., Wei, W., Jiang, J., Chung, K., and Yang, Y.: Hippo signaling is intrinsically regulated during cell cycle progression by APC/CCdh1  (PNAS direct submission). Proc Natl Acad Sci USA 2019;116:9423-9432.
  13. Choi, W., Kim, H., Kim, M., Cinar, R., Yi, H., Eun, H., Kim, S., Choi, Y., Lee, Y., Kim, S., Seo, W., Lee, J., Shim, Y., Kim, Y., Yang, K., Ryu, T., Hwang, J., Lee, C., Choi, H., Gao, B., Kim, W., Kim, S., Kunos, G., Jeong, W.: Glutamate/mGluR5 signaling in stellate cells drives endocannabinoid-mediated alcoholic steatosis. Cell Metabolism 2019; 30(5):877-889
  14. Gao, Y., Zhou, Z., Kim, S., Ren, T., Seo, W., Guillot, A., Ding, Y., Wu, R., Shao, S., Wang, X., He, Y., Wang, W., Feng, D., Xu, M., Zhong, W., Zhou, Z., Niu, J., Gao, B.: Alcohol suppresses T cell energy metabolism and cytokine production in ALDH2-deficient mice and humans: Roles of acetaldehyde and corticosterone. Gut 2019; 68:1311-1322.
  15. Kim, S., Feng, D., Guillot, A., Dai, S., Liu, F., Hwang, S., Parker, R., Seo, W., He, Y., Godlewski, G., Jeong, W., Lin, Y., Qin, X., Kunos, G., and Gao, B.: Adipocyte death preferentially induces liver injury and inflammation via the activation of CCR2+ macrophages and lipolysis. Hepatology 2019; 69:1965-1982 
  16. Guillot, A., Ren, T., Jourdan, T., Pawlosky, R., Han, E., Zhang, L., Koob, G., Gao, B.: Targeting liver aldehyde dehydrogenase-2 prevents heavy but not moderate alcohol drinking (PNAS Direct submission). Proc Natl Acad Sci USA 2019; 116(51):25974-25981
  17. He, Y., Hwang, S., Cai, Y., Kim, S., Xu, M., Yang, D., Guillot, A., Feng, D., Seo, W., Gao, B.: MicroRNA-223 ameliorates nonalcoholic steatohepatitis and cancer by targeting multiple inflammatory and oncogenic genes in hepatocytes. Hepatology 2019, 70:1150-1167
  18. Seo, W., Gao, Y., He, Y., Sun, J., Xu, H., Feng, D., Park, S., Cho, Y., Guillot, A., Ren, T., Wu, R., Wang, J., Kim, S., Hwang, S., Liangpunsakul, S., Yang, Y., Niu, J., Gao, B.: ALDH2 deficiency promotes alcohol-associated liver cancer by transferring harmful DNA via exosomes and activating oncogenic pathways. Journal of Hepatology 2019, 71:1000-1011.
  19. Ouyang, X., Zhang, J., Feng, D., Han, S., Cai, S., Garcia Martinez, I., Hoque, R., Chen, Y., Jiang, X., Wang, F., Gao, B., Torok, N., and Mehal, W.: Digoxin limits hepatic damage and inflammation through mitochondrial ROS suppression.  Cell Metabolism 2018;27(2):339-350
  20. Wang, M., Shen, G., Xu, L., Liu, X., Brown, J.M., Feng, D., Ross, R.A., Gao, B., Liangpunsakul, S., Ju, C.: Protective role of IL-1 receptor like 1 (ST2) in alcoholic liver disease. Journal of Hepatology 2018;68:109–117
  21. Zhou, Z., Xu, M., Cai, Y., Wang, W., Jiang, J., Varga, Z., Feng, F., Pacher, P., Kunos, G., Torok, N., Gao, B.: Interaction of neutrophils and hepatic stellate cells promotes fibrosis in a mouse model of steatohepatitis. Cellular and Molecular Gastroenterology and Hepatology 2018;5:399-413
  22. Li, H., Feng, D., Cai, Y., Liu, Y., Xu, M., Xiang, X., Zhou, Z., Xia, Q., Kaplan, M., Kong, X., Gao, B.: Hepatocytes and neutrophils cooperatively suppress bacterial infection by differentially regulating lipocalin-2 and neutrophil extracellular traps. Hepatology 2018, 68(4):1604-1620 
  23. Kim, W., Khan, S. K., Liu, Y., Xu, R., Park, O., Cha, B., Gao, B., Yang, Y.: Hepatic Hippo signaling inhibits pro-tumoral microenvironment to suppress hepatocellular carcinoma. Gut 2018, 67(9):1692-1703
  24. Ramirez, T., Li, Y., Yin, S., Xu, M., Feng, D., Zang, M., Mukhopadhyay, P., Varga, Z., Pacher, P., Gao, B., Wang, H.: Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating Sirtuin 1 expression in the liver. Journal of Hepatology 2017; 66:601-609
  25. Cai, Y., Xu, M., Koritzinsky, E., Zhou, Z., Wang, W., Cao, H., Yuen, P., Ross, R., Star, A. R., Liangpunsakul, S., Gao, B.: ER stress-dependent release of mtDNA enriched microparticles contribute acute-on-chronic alcoholic neutrophilia and hepatotoxicity. Journal of Clinical Investigation Insight 2017;2(14):e92634.
  26. Wang, W., Xu, M., Cai, Y., Zhou, Z., Cao, H., Mukhopadhyay, P., Pacher, P., Zheng, S., Gonzalez, F., Gao, B.: Inflammation is independent of steatosis in a model of steatohepatitis. Hepatology 2017; 66:108-123
  27. Li, M., He, Y., Zhou, Z., Ramirez, T., Gao, Y., Kang, X., Ross, R., Cao, H., Cai, Y., Xu, M., Feng, D., Liangpunsakul, S., Gao, B.: MicroRNA-223 ameliorates alcoholic liver injury by attenuating neutrophils in an IL-6-NCF-1 dependent mechanism. Gut 2017; 66:705-715
  28. He, Y., Feng, D., Li, M., Gao, Y., Ramirez, T., Kim, S., Ju, C., Wang, H., Li, J., Gao, B.: Hepatic mitochondrial DNA-TLR9-microRNA-223 forms a negative feedback loop to control acetaminophen-induced acute liver injury and inflammation. Hepatology 2017; 66:220-234
  29. Kim, W., Khan S., Gvozdenovic-Jeremic, J., Kim, Y., Dahlman1, J., Kim, H., Park, P., Ishitani, T., Jho, E., Gao, B., Yang, Y.: Hippo signaling interactions with Wnt/beta-catenin and Notch signaling repress liver tumorigenesis. Journal of Clinical Investigation 2017;127:137-152 
  30. Mukhopadhyay, P., Horváth, B., Rajesh, M., Varga, Z., Gariani, K., Ryu D, Cao, Z., Holovac, E., Park, O., Zhou, Z., Xu, MJ., Wang, W., Godlewski, G., Paloczi, J., Nemeth, BT., Persidsky, Y., Liaudet, L., Haskó, G., Bai, P., Boulares, H., Auwerx, J., Gao, B., and Pacher.: PARP inhibition protects against alcoholic steatohepatitis. Journal of Hepatology 2017; 66:589-600
  31. Xu, M., Cai, Y., Wang, H., Altamirano, J., Chang, B., Bertola, A., Odena, G., Lu, J., Tanaka, N., Matsusue, K., Matsubara, T., Mukhopadhyay, P., Kimura, S., Pal, P., Gonzalez, F., Bataller, R., and Gao, B.:  Fat-specific gene 27/Cide-c plays an important role in promoting alcoholic liver injury in mice and humans. Gastroenterology 2015; 149:1030-1041
  32. Feng, D., Dai, S., Liu, F., Ohtake, Y., Zhou, Z., Wang, H., Zhang, Y., Kearns, A., Peng, X., Zhu, F., Hayat, U., Li, M., He, Y., Xu, M., Zhao, C., Cheng, M., Zhang, L., Wang, H., Yang, X., Ju, C., Bryda, E., Gordon, J., Khalili, K., Hu, W., Li, S., Qin, X., Gao, B.: Cre-inducible human CD59 mediates rapid cell ablation after intermedilysin administration. Journal of Clinical Investigation 2016; 126:2321-2333 
  33. Oh, Y., Park, O., Swierczesca, M., Kim, T., Hamilton, J., Lim, S., Eom, H., Mastorakos, P., Clark Zhang, C., Jo, D., Han, S., Park, P., Jeon, O., Byun, Y., Kim, K., Hanes, J., Lee, K., Pomper, M., Gao, B., and Lee, S.: A systemically administered PEGylated TRAIL targets and eradicates activated hepatic stellate cells and reverses liver fibrosis and cirrhosis. Hepatology 2016; 64(1):209-23
  34. Xu, M., Feng, D., Wu, HL., Wang, H., Chan, Y., Kolls, J., Niels, B., Bo, P., Thorsten, B., Cowland,J., Mak, T., Kong, X., Gao, B.: The liver is the major source of elevated serum lipocalin 2 after bacterial infection or partial hepatectomy. Hepatology 2015; 61:692-702
  35. Mathews, S., Feng, D., Maricic, I., Ju., C., Kumar, V., Gao. B.: Invariant natural killer T cells promote chronic-binge ethanol-induced liver injury by recruiting neutrophils in mice. Cellular Molecular Immunology 2015; 13: 206-216
  36. Chang, B., Xu, M., Zhou, Z., Cai, Y., Li, M., Wang, W., Feng, D., Bertola, A., Wang, H., Kunos, G., Gao, B.: Short- or long-term high fat diet feeding plus acute ethanol binge synergistically induce steatohepatitis in mice: an important role for CXCL1. Hepatology 2015; 62:1070-85 
  37. Xu, M., Cai, Y., Wang, H., Altamirano, J., Chang, B., Bertola, A., Odena, G., Lu, J., Tanaka, N., Matsusue, K., Matsubara, T., Mukhopadhyay, P., Kimura, S., Pal, P., Gonzalez, F., Bataller, R., and Gao, B.:  Fat-specific gene 27/Cide-c plays an important role in promoting alcoholic liver injury in mice and humans. Gastroenterology 2015; 149:1030-1041
  38. Maricic, I., Sheng, H., Seki, E., Kisseleva, T., Chaturved, S., Molle, N., Mathews, S., Gao, B., and Kumar, V.: Inhibition of type I NKT cells by retinoids or following sulfaide-mediated activation of type II NKT cells attenuates alcoholic liver disease. Hepatology 2015 61:1357-69
  39. Kim, J., Hwang, J., Lee, D., Park, K., Kim, G., Jeong, E., Lee, Y., Go, M., Kim, D., Lee, S., Kim, B., Song, J., Roh, G., Gao, B., Kim, W.: Chronic ethanol consumption inhibits glucokinase transcriptional activity through the ATF3-PDX1-HDAC1 axis and triggers metabolic syndrome in vivo. Journal of Biological Chemistry 2014;289(39):27065-79
  40. Zhang, P., Tu, B., Wang, H., Cao, Z., Tang, M., Zhang, C., Gu, B., Li, Z., Wang, L., Yang, Y., Zhao, Y., Wang, H.,  Luo, J., Deng, X., Gao, B., Roeder, R., Zhu, W.: Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. Proc Natl Acad Sci USA 2014; 111(29):10684-10689
  41. Yin, S., Wang, H., Bertola, A., Feng, D., Xu, M., Wang, Y., and Gao, B.: Activation of invariant NKT cells inhibits liver regeneration via both IFN- and IL-4-dependent mechanisms. Hepatology 2014; 60:1356–1366 
  42. Feng, D., Wang, Y., Wang, H., Weng, H., Kong, X., Martin-Murphy, B., Li, Y., Park, O., Dooley, S., Ju, C., and Gao, B.: Acute and chronic effects of IL-22 on acetaminophen-induced liver injury. Journal of Immunology 2014;193(5):2512-2518.
  43. Kim, J., Reddy, J., Rhee, S., Gao, B., and Gonzalez, F.: Hepatic oxidative stress activates the Gadd45b gene via degradation of the transcriptional repressor STAT3. Hepatology 2014; 59(2):1094-1106
  44. Li, Y., Wong, K., Jiang, J., Giles, A., Lee, J., Adams, A., Kharitonenkov, A., Gao, B., Guarente, L., and Zang M.: Hepatic SIRT1 ameliorates steatosis and enhances fatty acid oxidation and ketogenesis by upregulating fibroblast growth factor 21. Gastroenterology 2014; 146(2):539-549
  45. Mukhopadhyay, P., Rajesh, M., Cao, Z., Horvath, B., Park, O., Wang, H., Erdelyi, K., Holovac, E., Wang, Y., Liaudet, L.,  Hamdaoui, N., Lafdil, F., Hasko, G., Szabo, C., Boulares, H., Gao, B., and Pacher, P.: Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis. Hepatology 2014;59(5):1998-2009
  46. Zhang, P., Tu, B., Wang, H., Cao, Z., Tang, M., Zhang, C., Gu, B., Li, Z., Wang, L., Yang, Y., Zhao, Y., Wang, H.,  Luo, J., Deng, X., Gao, B., Roeder, R., Zhu, W.: Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. Proc. Natl. Acad. Sci. USA 2014;111:10684-10689
  47. Kwon, H., Won,Y., Park,O., Gao, B.: Prednisolone treatment exacerbates hepatotoxin-induced acute liver injury by targeting glucocorticoid receptors in neutrophils and macrophages in mice. Hepatology 2014; 59:695-704
  48. Kwon, H., Won,Y., Park,O., Chang, B., Duryee, M., Thiele, G. E., Matsumoto, A., Singh, S., Abdelmegeed, M., Song, B., Kawamoto, T., Vasiliou, V., Thiele, G., Gao, B.: Aldehyde dehydrogenase 2 deficiency ameliorates alcoholic fatty liver but worsens liver inflammation and fibrosis in mice.  Hepatology 2014;60:146-157
  49. Bertola, A., Mathews, S., Wang, H., Ki, S., and Gao, B.: Chronic plus binge ethanol feeding model (the NIAAA model). Nature Protocols 2013;8:627-637
  50. Weng, H., Feng, D., Radaeva, S., Kong, X., Wang, L., Liu, Y., Li, Q., Shen, H., Gao, Y., Müllenbach, R., Munker, S., Huang, T., Chen, J., Zimmer, V., Lammert, F., Mertens, P., Cai, W., Dooley, S., Gao, B.: IFN-g inhibits liver progenitor cell expansion in HBV-infected patients and in 3,5-diethoxycarbonyl-1,4-dihydrocollidine-fed mice. Journal of Hepatology 2013,59(4):738-45
  51. Wang, H., Feng, D., Park, D., Yin, S., Gao, B.: Invariant NKT cell activation induces neutrophil accumulation and hepatitis: oppositely regulated by IL-4 and IFN-gamma. Hepatology 2013 58:1474-1485
  52. Bertola, A., Park, O., and Gao, B.: Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury: A critical role of E-selectin.  Hepatology 2013, 58:1814-1823
  53. Kong, X., Feng, D., Wang, H., Hong, F., Bertola, A., Wang, F., and Gao, B.: IL-22 induces hepatic stellate cell senescence and restricts liver fibrosis. Hepatology 2012 56:1150-1159
  54. Feng, D., Kong, X., Weng, H., Park, O., Wang, H., Dooley, S., Gershwin, E., and Gao, B.: IL-22 promotes liver progenitor cell proliferation in patients with viral hepatitis and in mice. Gastroenterology 2012 143:188-198
  55. Park, O., Wang, H., Weng, H., Feigenbaum, L., Li, H., Yin, S., Ki, S., Yoo, S., Dooley, S., Wang, F., Young, S., and Gao, B.:  In vivo consequences of liver-specific IL-22 expression: implications for human liver disease progression. Hepatology, 2011, 54:252-261
  56. Miller, A., Wang, H., Park, O., Horiguchi, N., Ki, S., Yin, S., Lafdil, F., and Gao, B.: Inflammation-associated hepatic IL-6/STAT3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in IL-10 deficient mice. Hepatology 2011 54:846-856
  57. Li, Y.,  Xu, S., Mihaylova, M., Zheng, B., Hou, X., Jiang, B., Park, O., Luo, Z., Lefai, E.,  Shyy, J., Gao, B., Wierzbicki, M., Verbeuren, T., Shaw, R., Cohen, R., Zang, M.: AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin resistant mice. Cell Metabolism 2011, 13:376-88
  58. Jeong, W., Park, O., Wang, L., Suh, Y., Byun, J., Park, S., Kim, J., Ko, H., Wang, H., Miller, A. and Gao, B.: Suppression of innate immunity (NK cells and IFN-gamma) in the late stages of liver injury. Hepatology 2011, 53:1342-1351
  59. Zhang, Z., Zhang, S., Zou, Z., Fan, R., Zhao, J., Li, B., Fu, J., Li, Z., Qin, E., Xu, X., Zhang, J., Zhou, C., Shi, M., Gao, B., Tian, Z., Wang, F.: Roles of NK cells in liver injury and fibrosis in patients with chronic HBV infection. Hepatology 2011, 53:73-85
  60. Ki, S., Park, O., Zheng, M., Kolls, J., Batller, R., and Gao, B.: IL-22 treatment ameliorates alcoholic liver injury in a murine model of chronic plus binge drinking. Hepatology 2010, 52:1291-300
  61. Zhang. X., Tachinana, S., Wang, H., Williams, G., Gao, B., and Sun, Z.: IL-6 is an essential mediator for mitochondrial DNA repair in alcoholic liver injury in mice. Hepatology 2010, 52:2137-2147
  62. Kim H, Xiao C, Wang R, Lahusen T, Xu X, Vassilopoulos A, Vazquez-Ortiz G, Jeong W, Park O, Ki S, Gao B, Deng CX.: Sirt6 deacetylase negatively regulates glycolysis and triglyceride synthesis and prevents fatty liver formation in mice. Cell Metabolism 2010, 12:224-236
  63. Horiguchi N, Lafdil F, Miller AM, Park O, Wang H, Rajesh M, Mukhopadhyay P, Fu X, Pacher P, Gao, B.: Dissociation between hepatic inflammation and necrosis induced by CCl4 in myeloid cell specific STAT3 knockout mice.   Hepatology 2010, 51:1724-34
  64. Wang, H., Lafdil, F., Park, O., Shen, K., Horiguchi, N., Yin, S., Fu, X., Kunos, G., Gao, B.: Interplay of hepatic and myeloid STAT3 in facilitating liver regeneration via tempering innate immunity.  Hepatology 2010, 51:1354-1362
  65. Hong, H., Mak, K., Topol, L., Yun, K., Hu, J., Garrett, L., Chen, Y., Park, O., Chang, J., Simpson, R., Wamg, C., Gao, B., Jiang, J., Yang, Y.: Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Natl Acad Sci USA 2010, 107:1431-6
  66. Park, O., Jeong, W., Wang, L., Wang, H., Lian, Z., Gershwin, E., and Gao, B: Diverse roles of invariant NKT cells in liver injury and fibrosis induced by carbon tetrachloride.  Hepatology 2009, 47:571-580
  67. Lafdil, F., Wang, H., Park, O., Zhang, W., Moritoki, Y., Fu, X., Gershwin, M., Lian, Z., Gao, B.: Myeloid STAT3 inhibits T-cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production. Gastroenterology 2009, 137:2125-35
  68. Hu, W., Ferris, S., Tweten, R., Wu, G., Radaeva, S., Gao, B., Bronson, R., Halperin, J., Qin, X.:  Conditional, rapid and targeted ablation of cells expressing human CD59 in transgenic mice by intermedilysin. Nature Medicine 2008;14, 98 – 103
  69. Horiguchi, N., Wang, L., Mukhopadhyay, P., Jeong, W., Lafdil, F., Osei-Hyiaman, D., Moh, A., Fu, X., Pacher, P., Kunos, G., Gao, B.: Cell-dependent pro- and anti-inflammatory role of STAT3 in alcoholic liver injury. Gastroenterology 2008;134:1148-1158
  70. Chuang, Y., Lian, Z., Yang, G., Shu, S., Moritoki, Y., Ridgway, M., Kronenberg, M., Flavell, R., Gao, B., and Gershwin, E.: CD1d-restricted NKT cells exacerbate liver injury in a TGF-beta receptor II dominant-negative mouse model of primary biliary cirrhosis. Hepatology 2008;47:571-580
  71. Jeong, W., Park, O., Gao, B.:  Abrogation of anti-fibrotic effects of NK/IFN-gamma contributes to alcohol acceleration of liver fibrosis. Gastroenterology 2008, 134:248-258
  72. Jeong W, Osei-Hyiaman, D., Park, O., Liu, J., Bátkai, S., Mukhopadhyay, P., Horiguchi, N., Harvey-White, J., Marsicano, G., Lutz, B., Gao, B., Kunos, G.: Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic liver disease. Cell Metabolism 2008; 7:227-35.
  73. Radaeva, S., Wang, L., Radaev, S., Jeong, W., Park, O., and Gao, B.: Retinoic acid signaling upregulates natural killer cell activating ligand RAE1 in hepatic stellate cells. American Journal of Physiology (GI and Liver) 2007, 293:G809-816.
  74. Cui, Y., Hosui, A., Sun, R., Shen, K., Gavrilova, O., Chen, W., Cam, M., Gao, B., Robinson, G., Hennighausen, L.: Inactivation of hepatic Stat5a/b results in aberrant GH-induced activation of Stat1 and Stat3, hepatosteatosis, and diminished liver regeneration. Hepatology 2007;46:504-513
  75. Batkai, S., Osei-Hyiaman, D., Pan, H., El-Assal, O., Rajesh M., Mukhopadhyay, P., Hong, F., Harvey-White, J., Jafi, A., Hasko, G., Huffman, J., Gao, B., Kunos, G., Pacher, P.: Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury.     FASEB Journal 2007, 21:1788-800
  76. Sun R., Park, O., Horiguchi, N, Kulkarni, S., Jaruga, B., Jeong, W., Sun, H., Radaeva, S., and Gao, B:. STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice.  Hepatology 2006, 44:955-966
  77. Jeong, W., Park, O., Radaeva, S., and Gao, B: STAT1 inhibits liver fibrosis through attenuating stellate cell activation and stimulating NK cell killing of activated stellate cells.  Hepatology 2006, 44:1441-1451
  78. Radaeva, S., Sun, R., Jaruga, B., Nguyen, V., Tian, Z., Gao B.: Natural killer cells ameliorate liver fibrosis through killing activated stellate cells in RAE1/NKG2D- and TRAIL-dependent manners. Gastroenterology 2006, 130: 435-452.
  79. Xu, X., Kobayashi, S., Qiao, W., Li, C., Xiao, C., Radaeva, S., Stiles, B., Wang, R., Ohara, N., Yoshino, T., LeRoith, D., Torbenson, M., Gores, G., Wu, H., Gao, B., and Deng, C. Induction of cholangiocellular carcinoma by liver specific disruption of Smad4 and Pten in mice.  Journal of Clinical Investigation 2006, 116:1843-1852
  80. Sun R., and Gao, B.: Negative regulation of liver regeneration by innate immunity (NK/IFN-gamma). Gastroenterology 2004, 127, 1525-1539
  81. Radaeva, R., Sun, R., Pan, H., Hong, F., and Gao, B.: Interleukin-22 (IL-22) plays a protective role in T cell hepatitis: IL-22 is a survival factor for hepatocytes via activation of STAT3. Hepatology 2004, 39:1332-1342.
  82. Hong, F., Radaeva, S., Pan, H., Tian, Z., Veech, R., and Gao, B.: Interleukin-6 treatment alleviates steatosis and ischemia/reperfusion injury in mice with fatty liver disease. Hepatology 2004, 40: 933-941.
  83. Jaruga, B., Hong, F., Sun, R., Radaeva, S., and Gao, B.: Crucial Role of IL-4/STAT6 in T cell-mediated hepatitis: Upregulating eotaxins and IL-5, and recruiting leukocytes. J. Immunol.  2003, 171: 3233-3244  
  84. Sun, Z., Klein, A. S., Radaeva, S., Hong, F., El-Assal, O., Jaruga, B., Pan, H., Batkai, S., Tian, Z., Hoshino, S., Kunos, G., Diehl, A., and Gao, B.: In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats. Gastroenterology 2003, 125:202-215.
  85. Radaeva, S., Jaruga, B., Hong, F., Kim, W. H., Fan, S., Cai, H., Strom S., Liu, Y., El-Assal, O., and Gao, B.: Interferon-a activates multiple STAT signals and downregulates c-Met in primary human hepatocytes. Gastroenterology 2002, 122:1020-1034.
  86. Hong, F., Jaruga, B., Kim, W. H., Radaeva, S., Tian, Z., El-Assal, O., Nguyen, V., and Gao, B.: Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS. Journal of Clinical Investigation 2002, 110: 1503-1513.
  87. Nguyen, V. N., and Gao, B.: Expression of interferon-alpha signaling components in human alcoholic liver disease. Hepatology 2002, 35:425-432
  88. Hong, F., Kim, W. H., Tian, Z., Jaruga, B., Ishac, E., Shen, X., and Gao, B.: Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of Bcl-2 and Bcl-x(L) proteins. Oncogene  2002, 21:32-43
  89. Hong, F., Nguyen, V. N., and Gao, B.: Tumor necrosis factor alpha attenuates interferon alpha/beta signaling in the liver: involvement of SOCS3 and SHP2 and implication in resistance to interferon therapy.  FASEB Journal 2001, 15:1595-1597
  90. Kim, W. H., Hong, F., Jaruga, B., Hu, Z., Fan, S., Liang, J., and Gao, B.: Additive activation of NF-B by ethanol, hepatitis B protein X and HCV core protein: Involvement of TNFalpha receptor 1-independent and –dependent mechanisms. FASEB Journal 2001, 15:2551-2553
  91. Tian, Z. G., Shen, X. N., Hong, F., and Gao, B.: IL-1 beta attenuates interferon alpha/beta-induced antiviral activity and STAT1 activation in the liver: involvement of proteasome-dependent mechanism. Journal of Immunology 2000, 165:3959-3965
  92. Shen, X. N., Tian, Z. G., Holtzman, M. J., and Gao, B.: Cross-talk between interleukin 1 (IL-1beta) and IL-6 signaling pathways: IL-1 inhibits IL-6-activated STAT1 by a ubiquitin-proteasome dependent mechanism. Biochemical Journal 2000, 352:913-919
  93. Liu, J., Shen, X., Nguyen, V. A., Kunos, G., and Gao, B.: 1 Adrenergic agonist induction of p21Waf1/cip1 mRNA stability in transfected HepG2 cells correlates with the increased binding of an AU-rich element binding factor. Journal of Biological Chemistry 2000, 275:11846-11851

Review Articles:

  1. Wang, X., He, Y., Mackowiak, B., and Gao, B.: MicroRNAs as regulators, biomarkers, and therapeutic targets in liver diseases. Gut 2020 Oct 30:gutjnl-2020-322526. doi: 10.1136
  2. He, Y., Hwang, S., Ahmed, Y., Feng, D., Li, N., Ribeiro, M., Lafdil, F., Kisseleva, T., Szabo, G., Gao, B.:  Immunopathobiology and therapeutic targets related to cytokines in liver diseases. Cellular and Molecular Immunology, 2021 Jan;18(1):18-37
  3. Avila, M., Dufour, J., Gerbes, A., Zoulim, F., Bataller, R., Burra, P., Cortez-Pinto, H., Gao, B., Gilmore, I., Mathurin, P., Moreno, C., Poznyak, V., Schnabl, B., Szabo, G., Thiele, M., Thursz, M.: Recent advances in alcohol-related liver disease (ALD): summary of a Gut roundtable meeting. Gut 2020; 69(4):764-780
  4. Gao, B., Ahmed, M., Nagy, L., and Tsukamoto, H.: Inflammatory pathways in alcoholic steatohepatitis. Journal of Hepatology 2019; 70:249-259
  5. Parker, R., Kim, S., and Gao, B.: Alcohol, adipose tissue, and liver disease: Mechanistic links and clinical considerations. Nature Reviews in Gastroenterology and Hepatology  2018;15(1):50
  6. Seitz, H., Bataller, R., Cortez-Pinto, H., Gao, B., Gual, A., Lackner, K., Mathurin, P., Mueller, S., Szabo, G., Tsukamoto, H.: Alcoholic liver Disease. Nature Reviews Disease Primers 2018; Aug 16;4(1):16
  7. Gao, B., Tsukamoto, H.: Inflammation in alcoholic and nonalcoholic liver disease: friend or foe? Gastroenterology 2016; 150(8):1704-9
  8. Mandrekar, P., Bataller, R., Tsukamoto, H., Gao, B.: Alcoholic hepatitis: translational approaches to develop targeted therapy. Hepatology 2016; 64(4):1343-55
  9. Tian, Z., Wang, Y., Gao, B.: Natural killer cells in liver disease. Hepatology 2013, 57:1654-1662
  10. Gao, B., Lafdil, F., Wang, H., Feng, D.: The STAT proteins: key regulators of antiviral response, inflammation and tumorigenesis in the liver. Journal of Hepatology 2012, 57:430-41
  11. Wang, H., Gao, B., Zakhari, S., and Nagy, L.: Inflammation in alcoholic liver disease. Annual Reviews of Nutrition 2012, 32:343-68
  12. Gao, B., Bataller, R.: Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011,141:1572-1585
  13. Gao, B., Jeong, W., and Tian, Z.: Liver: an organ with predominant innate immunity. Hepatology 2008; 47:729-736
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