Alcoholic liver disease affects millions of people worldwide and it remains to be a therapeutic challenge for clinicians. Activation of the inflammatory cascade via gut-derived lipopolysaccharide (LPS) contributes to alcoholic liver disease via induction of pro-inflammatory cytokines induction in Kupffer cells. Micro-RNA-155 (miR-155), small non-coding RNA molecule, is important in regulation of inflammation. Our preliminary data demonstrate that chronic alcohol up-regulates miR155 in macrophages in vitro as well as in vivo in the liver and in isolated Kupffer cells and this miR155 increase contributes to inflammation in alcoholic liver disease. We hypothesize that miRNAs not only play a role in the pathomechanism of alcoholic liver disease but also represent therapeutic targets and potential biomarkers. Specifically, we postulate that alcohol-induced miR-155 is a mediator of KC sensitization to gut-derived LPS, and that alcohol-induced miR-155 increase leads to amplification of pro-inflammatory cytokine production by KC. We further hypothesize that inhibition of miR-155 in the liver and/or in Kupffer cells will ameliorate alcohol-induced liver disease. Based on our preliminary data demonstrating increased serum levels of miR-155 and miR-122 in alcohol-induced liver injury, we propose that these serum miRNAs may serve as biomarkers of alcohol-induced liver damage. These hypotheses will be tested in the following Specific Aims: 1. To evaluate the mechanistic role of miR155 in alcoholic liver injury;2. To delineate the mechanisms by which chronic alcohol increases miR-155 levels in alcoholic liver disease;3. To explore the therapeutic potential of in vivo inhibition of miR155 in the development of alcoholic liver disease. Results from the proposed experiments will provide new insights into the role of miRNAs in alcoholic liver disease, identify potential early biomarkers of inflammation and liver damage in ALD and provide reclinical evaluation of novel therapeutic intervention via target-specific and cell-specific delivery of a miRNA-antagonist.

Public Health Relevance

The impact of new discoveries from this proposed research is expected to be highly significant. For example, identification of miRNAs as biomarkers of liver damage could revolutionalize clinical diagnostics and disease prognosis. The proposed therapeutic intervention, if successful could be then directly translated into human clinical trials in the underserved area of alcoholic steatohepatitis.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAA1-JJ (01))
Program Officer
Murray, Gary
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Bala, Shashi; Csak, Timea; Saha, Banishree et al. (2016) The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis. J Hepatol 64:1378-87
Ambade, Aditya; Satishchandran, Abhishek; Szabo, Gyongyi (2016) Alcoholic hepatitis accelerates early hepatobiliary cancer by increasing stemness and miR-122-mediated HIF-1α activation. Sci Rep 6:21340
Bala, Shashi; Csak, Timea; Momen-Heravi, Fatemeh et al. (2015) Biodistribution and function of extracellular miRNA-155 in mice. Sci Rep 5:10721
Szabo, Gyongyi (2015) Gut-liver axis in alcoholic liver disease. Gastroenterology 148:30-6
Momen-Heravi, Fatemeh; Bala, Shashi; Kodys, Karen et al. (2015) Exosomes derived from alcohol-treated hepatocytes horizontally transfer liver specific miRNA-122 and sensitize monocytes to LPS. Sci Rep 5:9991
Saha, Banishree; Bala, Shashi; Hosseini, Nooshin et al. (2015) Krüppel-like factor 4 is a transcriptional regulator of M1/M2 macrophage polarization in alcoholic liver disease. J Leukoc Biol :
Szabo, Gyongyi; Satishchandran, Abhishek (2015) MicroRNAs in alcoholic liver disease. Semin Liver Dis 35:36-42
Csak, Timea; Bala, Shashi; Lippai, Dora et al. (2015) MicroRNA-155 Deficiency Attenuates Liver Steatosis and Fibrosis without Reducing Inflammation in a Mouse Model of Steatohepatitis. PLoS One 10:e0129251
Csak, Timea; Bala, Shashi; Lippai, Dora et al. (2015) microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis. Liver Int 35:532-41
Lippai, Dora; Bala, Shashi; Catalano, Donna et al. (2014) Micro-RNA-155 deficiency prevents alcohol-induced serum endotoxin increase and small bowel inflammation in mice. Alcohol Clin Exp Res 38:2217-24

Showing the most recent 10 out of 15 publications