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.
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.
- 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.
- 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.
- 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.
- 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.
- Tian, Z., Wang, Y., Gao, B.: Natural killer cells in liver disease. Hepatology 2013, 57:1654-1662
- 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
- Wang, H., Gao, B., Zakhari, S., and Nagy, L.: Inflammation in alcoholic liver disease. Annual Reviews of Nutrition 2012, 32:343-68
- Gao, B., Bataller, R.: Alcoholic liver disease: pathogenesis and new therapeutic targets Gastroenterology 2011,141:1572-1585
- Gao, B., Jeong, W., and Tian, Z.: Liver: an organ with predominant innate immunity. Hepatology 2008; 47:729-736
- 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-g and IL-4-dependent mechanisms. Hepatology 2014 in press
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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-g) in the late stages of liver injury. Hepatology 2011, 53:1342-1351
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Jeong, W., Park, O., Gao, B.: Abrogation of anti-fibrotic effects of NK/IFN-g contributes to alcohol acceleration of liver fibrosis. Gastroenterology 2008, 134:248-258
- 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
- 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.
- 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-b receptor II dominant-negative mouse model of primary biliary cirrhosis. Hepatology 2008;47:571-580
- 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
- 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
- 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.
- 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. J. Clin. Invest. 2006, 116:1843-1852
- Sun R., and Gao, B.: Negative regulation of liver regeneration by innate immunity (NK/IFN-g). Gastroenterology 2004, 127, 1525-1539
- 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.
- 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.
- 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
- 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.
- 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.
- 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. J. Clin. Invest. 2002, 110: 1503-1513.
- Wang, H., and Gao, B.: miRNAs control hepatocarcinogenesis by regulating hepatocyte nuclear factor 4a-inflammatory signal feedback loops (Editorial). Hepatology, 2014 in press
- Gao, B., and Xu, M.: Chemokines and alcoholic hepatitis: are they good therapeutic targets? (Editorial) Gut, 2014, in press
- Mathews, S., and Gao, B.: Therapeutic potential of interleukin 1 inhibitors in the treatment of alcoholic liver disease (Hepatology Elsewhere) Hepatology, 2013,57:2078-2080
- Bataller, R., and Gao, B.: Dissecting the functions of CB1 receptors in chronic liver diseases (Editorial) Gut, 2013, 62:957-958
- Gao, B., and Waisman A.: Th17 cells regulate liver fibrosis by targeting multiple cell types: Many birds with one stone. Gastroenterology 2012, 143:536-539
- Gao, B., and Bertola A.: Natural killer cells take two Tolls to destruct bile ducts. Hepatology 2011, 53:1076-1079
- Gao, B.: Innate immunity and steatohepatitis: A critical role of another Toll (TLR9). Gastroenterology 2010, 139:27-30
- Gao, B.: NKG2D, its ligands and liver disease – good or bad? Hepatology 2010, 51:8-11
- Danese, S., and Gao, B.: IL-6: A therapeutic Jekyll and Hyde in gastrointestinal and hepatic diseases. Gut 2010, 59:149-151
- Kunos, G., Osei-Hyiaman, D., Bátkai, S., and Gao, B.: Cannabinoids hurt, heal in cirrhosis. Nature Medicine 2006, 12:608-610