Alcoholic liver disease (ALD) and alcoholic hepatitis (AH) are the leading causes of liver cirrhosis and liver- related death worldwide. MicroRNAs modulate the pathogenesis of ALD by regulating hepatocyte function, inflammatory cell activation and liver fibrosis. Our research revealed that alcohol-induced increase in miR-155 interferes with key elements in the pathogenesis of ALD including steatosis, liver damage and inflammation. Based on these data we hypothesize that miR-155 plays a cell-specific role in ALD both in hepatocytes and immune cells and represents a potential therapeutic target in ALD. We also discovered that circulating miR-155 is packaged in exosomes and that alcohol increases exosome release and our novel data show that alcohol- induced exosome production is attenuated in miR-155 deficient mice. We found that alcohol-induced upregulation of miR-155 promotes autophagy, both in macrophages and hepatocytes, by targeting key molecules in the autophagy pathway. Thus, we propose that exosome production is linked to impaired autophagy flux and it may represent a mechanism to maintain cellular homeostasis in alcohol exposed cells.
The specific aims of this proposal will! 1) delineate the cell-specific role of miR-155 in ALD in hepatocytes and innate immune cells using hepatocyte- and bone marrow-derived cell-specific deletion of miR-155 (cre-lox recombination based) in vivo after chronic alcohol feeding (ALD) and acute binge on chronic alcohol (AH) in mice; 2) test the role of miR-155 in alcohol-induced exosome cargo and the biological effect of exosome- mediated transfer of miR-155 on hepatocyte-macrophage crosstalk; 3) investigate the effect of alcohol and miR-155 on the mechanistic inter-relationship between impaired autophagy flux and exosome production/biogenesis in hepatocytes and immune cells; and 4) evaluate the effect of inhibition of miR-155 on autophagy, exosome production and liver injury in a mouse model of ALD and AH using an AAV8-mediated miR-155 tough decoy to inhibit miR-155, in vivo. Our experiments will provide novel insights into key intracellular processes by which miR-155 regulates autophagy and exosome production for better understanding of the pathophysiology of alcoholic liver disease and alcoholic hepatitis.

Public Health Relevance

Alcoholic liver disease (ALD) and its clinically most devastating presentation, alcoholic hepatitis, represent the most common cause of chronic liver disease across all continents. This research will test new cellular mechanisms in ALD such as autophagy and exosome production and their regulation by microRNA-155, a non-coding RNA, to discover how to liver cell damage and inflammation occur. Our research will identify and test candidate molecules for novel interventions in the mouse model of ALD using gene therapy approaches that will provide basis for future studies in patients with alcoholic hepatitis.!

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Wang, Joe
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Beth Israel Deaconess Medical Center
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Satishchandran, Abhishek; Ambade, Aditya; Rao, Sitara et al. (2018) MicroRNA 122, Regulated by GRLH2, Protects Livers of Mice and Patients From Ethanol-Induced Liver Disease. Gastroenterology 154:238-252.e7
Wang, Xiaojing; de Carvalho Ribeiro, Marcelle; Iracheta-Vellve, Arvin et al. (2018) Macrophage-Specific Hypoxia-Inducible Factor-1? Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis. Hepatology :
Bala, Shashi; Szabo, Gyongyi (2018) TFEB, a master regulator of lysosome biogenesis and autophagy, is a new player in alcoholic liver disease. Dig Med Res 1:
Bala, Shashi; Csak, Timea; Kodys, Karen et al. (2017) Alcohol-induced miR-155 and HDAC11 inhibit negative regulators of the TLR4 pathway and lead to increased LPS responsiveness of Kupffer cells in alcoholic liver disease. J Leukoc Biol 102:487-498
Iracheta-Vellve, Arvin; Petrasek, Jan; Gyongyosi, Benedek et al. (2016) Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes. J Biol Chem 291:26794-26805
Ambade, Aditya; Satishchandran, Abhishek; Szabo, Gyongyi (2016) Alcoholic hepatitis accelerates early hepatobiliary cancer by increasing stemness and miR-122-mediated HIF-1? activation. Sci Rep 6:21340
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
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 97:963-973
Sanyal, Arun J; Gao, Bin; Szabo, Gyongyi (2015) Gaps in Knowledge and Research Priorities for Alcoholic Hepatitis. Gastroenterology 149:4-9
Bala, Shashi; Csak, Timea; Momen-Heravi, Fatemeh et al. (2015) Biodistribution and function of extracellular miRNA-155 in mice. Sci Rep 5:10721

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