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Research

The NIAAA is the lead agency for U.S. research on the causes, consequences, prevention and treatment of alcohol use disorder and alcohol-related problems.

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Laboratory of Liver Diseases

Contact Information

  • Office: 301.443.3998
  • Fax: 301 480.0257

Overview of the Lab

Our laboratory has been actively investigating basic liver biology and liver immunology. By using the knowledge gained through these studies, we are investigating the immunological aspects and molecular pathogenesis of alcohol-associated liver disease (ALD) and liver cancer, and exploring novel therapeutic targets for the treatment of these maladies.

Recent Cover Stories

 

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August 2023 JCI Cover image featuring research from NIAAA LLD

Monocyte-derived macrophages repair necrotic liver lesions. Journal of Clinical Investigation Aug. 2023. 

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2022 JCI Cover image featuring research from NIAAA LLD

 

Distinct histopathological phenotypes of severe alcoholic hepatitis. Journal of Clinical Investigation July 2022.

Research Projects

Basic liver immunology and liver biology

The liver is the most important metabolic organ and is also the only mammalian organ that can fully regenerate after partial resection or injury. The liver has long been recognized to be immunologically privileged as evidenced by relative success with liver transplant. In addition, the liver has strong innate immunity that effectively and quickly defend against potentially toxic agents from the gut without launching harmful immune responses (Gao et al. 2008). Over the last two decades, our lab has been actively characterizing liver innate immune cells and cytokines produced by these cells, and exploring their functions in liver injury, regeneration, fibrosis, and cancer (He et al., 2021). Our recent studies have revealed that liver resident macrophages (Kupffer cells) regenerate after partial hepatectomy (Ahmed et al. 2021), and that  macrophages play a key role in promoting necrotic liver lesion resolution (Feng et al., 2023) and promoting acute bile duct injury (Guillot et al. 2021).

Alcohol-associated liver disease (ALD)

ALD is a major cause of chronic liver diseases, leading to cirrhosis and liver cancer. The latest report from our institute shows that liver cirrhosis was the 11th leading cause of death in the USA, accounting for a total of 47,919 deaths in 2019, and 50.3% were alcohol related (https://www.niaaa.nih.gov/sites/default/files/surveillance-report118.pdf). The spectrum of ALD includes steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Patients with underlying ALD and excessive alcohol intake may develop acute alcohol-associated hepatitis, a form of acute-on-chronic liver injury with the typical clinical syndrome jaundice (Gao and Bataller, 2011). 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 clinical investigators to conduct translational research on the pathogenesis and novel therapeutic targets for ALD with focusing on the following projects.

  1. Characterizing inflammation in ALD: Inflammation plays a key role in ALD progression, but its role still remains largely obscure (Gao et al., 2019). Our laboratory has been actively characterizing liver inflammation and exploring its functions in mice and patients with ALD by using multiplex immunofluorescence staining, bulk RNA sequencing, single cell RNA sequencing, and other cutting-edge technologies (Ma et al., 2022). We are also using experimental models such as chronic-plus-binge ethanol feeding (Bertola et al., 2013) to explore the functions of inflammation in ALD.
  2. Novel therapeutic targets of ALD: Despite the profound economic and health impact of ALD, there are still no FDA-approved therapies for ALD. Our laboratory has been comprehensively investigating hepatoprotective factors in ALD and involving in translating these findings into new therapies for ALD. Particularly, we first discovered interleukin-22 (IL-22) as a key survival factor for hepatocytes (Radaeva et al., 2004, Pan et al., 2004), and subsequently characterized IL-22 biology in the liver (Hwang et al., 2023). These studies led to a phase IIb trial showing a promising result of IL-22 therapy in alcohol-associated hepatitis (Arab et al. 2019). IL-22 clinical trials are ongoing for the treatment of acute-on-chronic liver failure including alcohol-associated hepatitis.
  3. Characterizing ALDH2 deficiency-associated ALD: Aldehyde dehydrogenase 2 (ALDH2) is the major enzyme that metabolizes acetaldehyde produced from alcohol metabolism. Approximately 30~40% 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 have been actively characterizing ALD in mice and human with ALDH2 deficiency (Seo et al., 2019, Gao et al., 2019).

Characterizing tumor microenvironment and liver cancer

Chronic alcohol consumption is a leading cause of liver cancer, but the underlying mechanisms remain obscure. We have been actively studying tumor microenvironment in alcohol-associated liver cancer (Fu et al., 2023) and how alcohol consumption affects tumor microenvironment.

Lab Members

Selected Publications

Feng, D., Xiang, X., Guan, Y., Guillot, A., Lu, H,, Chang, C., He, Y., Wang, H,, Pan, H., Ju, C., Colgan, S., Tacke, F., Wang, X., Kunos, G. and Gao, B.: Monocyte-derived macrophages orchestrate multiple cell interaction to repair necrotic liver lesions. Journal of Clinical Investigation 2023; 133(15):e166954. doi: 10.1172/JCI166954

Fu, Y., Mackowiak, B., Feng, D., Lu, H., Guan, Y., Lehner, T., Pan, H., Wang, X., He, Y., and Gao, B.: MicroRNA-223 attenuates hepatocarcinogenesis by blocking hypoxia-driven angiogenesis and immunosuppression. Gut 2023, 72(10):1942-1958

Ma, J., Guillot, A., Yang, Z., Mackowiak, B., Hwang, S., Park, O., Peiffer, B., Ahmadi, A., Melo, L., Kusumanchi, P., Huda, N., Saxena, R., He, Y., Guan, Y., Feng, F., Sancho-Bru, P., Zang, M., Cameron, A., Bataller, R., Tacke, F., Sun, Z., Liangpunsakul, S., Gao, B.: Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure. Journal of Clinical Investigation 2022, 132(14):e157780

Guillot, A., Guerri, L., Feng, D., Kim, S., Paloczi, J., He, Y., Schuebel, K., Dai, S., Liu, F., Pacher, P., Kisseleva, T., Qin, X., Goldman, D., Tacke, F., Gao, B.: Bile acid-activated macrophages promote biliary epithelial cell proliferation through integrin αvβ6 upregulation following liver injury. Journal of Clinical Investigation 2021, 131(9):132305

He, Y., Feng, D., Hwang, S., Mackowiak, B., Wang, X., Xiang, X., Rodrigues, R., Jin, M., Ren, T., Fu, F., Ait-Ahmed, Y., Xu, M., Liangpunsakul, S., and Gao, B.:  Interleukin-20 exacerbates acute hepatitis and bacterial infection by downregulating IκBζ target genes in hepatocytes. Journal of Hepatology 2021, 75:163-176

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 2021,131(3):e141513

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

Representative Previous Publications

Pan H, Radaeva, S., Hong, F., and Gao, B.: Hydrodynamic gene delivery of interleukin-22 protects the mouse liver from Concanavalin A-, carbon tetrachloride-, and Fas ligand-induced injury via activation of STAT3. Cellular Molecular Immunology 2004, 1:43-49

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

  • These two papers first reported the hepatoprotective function of IL-22

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, 72:441-453

  • A clinical trial revealed promising results of IL-22 therapy for alcohol-associated hepatitis

Ki, S., Park, O., Zheng, M., Kolls, J., Bataller, R., and Gao, B.: IL-22 treatment ameliorates alcoholic liver injury in a murine model of chronic plus binge drinking.  Hepatology 2010, 52 (4):1291-300

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

  • These two papers established and described the chronic-plus-binge model

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. Proceedings of the National Academy of Sciences of the USA 2019, 116:25974-25981

  • This paper suggests that the liver only partially contributes to ethanol metabolism

Selected Review Articles:

Wang, X., He, Y., Mackowiak, B., and Gao, B.: MicroRNAs as regulators, biomarkers, and therapeutic targets in liver diseases. Gut 2021, 70:784–795

Gao, B., Ahmed, M., Nagy, L., and Tsukamoto, H.: Inflammatory pathways in alcoholic steatohepatitis. Journal of Hepatology 2019, 70:249-259

Gao, B., Tsukamoto, H.: Inflammation in alcoholic and nonalcoholic liver disease: friend or foe? Gastroenterology 2016, 150(8):1704-9

Gao, B., Bataller, R.: Alcoholic liver disease: pathogenesis and novel 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

See full publications: https://www.ncbi.nlm.nih.gov/myncbi/bin.gao.2/bibliography/public/

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