Extracellular Vesicles in Alcoholic Liver Injury
Alcoholic liver disease (ALD) is one of the most common forms of chronic liver disease in the world; it is a major cause of chronic illness and mortality associated with alcohol over-consumption. ALD represents a broad spectrum of liver injury, such as hepatocyte cell death, liver inflammation, angiogenesis, and fibrosis leading to cirrhosis and hepatocellular carcinoma. Chronic ethanol consumption results in hepatic lipid accumulation and increases cell stress, which leads to inflammation and liver injury during the progression of ALD. It has been shown that crosstalk between hepatocytes and non-parenchymal cells is significantly important. The identifying factors that communicate stress signals from hepatocytes, and may initiate and perpetuate the inflammatory reaction responsible for liver injury and disease progression from steatohepatitis to cirrhosis may have a tremendous biomedical impact. Furthermore, the elucidation of these molecular mechanisms of crosstalk may allow for the identification of an individualized therapeutic approach in the treatment of patients with different stages of ALD and for the development of biomarkers to diagnose ALD progression. Recently, extracellular vesicles (EVs) have been identified as cell-to-cell communicators, the cellular contents of which contain proteins, lipids, and RNAs from stressed/activated cells and transfer this cellular payload to target cells. In this chapter, we will focus on current reports of EV function, how they are involved in the molecular pathogenesis of ALD, and EV biomarkers using EV composition.
KeywordsExtracellular vesicles Alcoholic liver injury ALD ASH AH
This work was partially supported by JSPS KAKENHI Grant Number JP16H06872 to AE and JSPS KAKENHI Grant Number JP17K09419 to YT.
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
- 8.Yanez-Mo M, Siljander PR, Andreu Z, Zavec AB, Borras FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015;4:27066. https://doi.org/10.3402/jev.v4.27066.CrossRefPubMedGoogle Scholar
- 11.Eguchi A, Lazaro RG, Wang J, Kim J, Povero D, Willliams B, Ho SB, Starkel P, Schnabl B, Ohno-Machado L, et al. Extracellular vesicles released by hepatocytes from gastric infusion model of alcoholic liver disease contain a MicroRNA barcode that can be detected in blood. Hepatology. 2017;65:475–90. https://doi.org/10.1002/hep.28838.CrossRefPubMedGoogle Scholar
- 12.Verma VK, Li H, Wang R, Hirsova P, Mushref M, Liu Y, Cao S, Contreras PC, Malhi H, Kamath PS, et al. Alcohol stimulates macrophage activation through caspase-dependent hepatocyte derived release of CD40L containing extracellular vesicles. J Hepatol. 2016;64:651–60. https://doi.org/10.1016/j.jhep.2015.11.020.CrossRefPubMedGoogle Scholar
- 13.Eguchi A, Kim J, Ohno-Machado L, Tsukamoto H, Feldstein AE. Hepatocytes from mice on intragastric feeding model of alcoholic steatohepatitis release extracellular vesicles with specific microRNA cargo that modulate hepatic stellate cell and macrophage phenotype. Hepatology. 2015;62:266A–7A.Google Scholar
- 14.Cai Y, Xu MJ, Koritzinsky EH, Zhou Z, Wang W, Cao H, Yuen PS, Ross RA, Star RA, Liangpunsakul S, et al. Mitochondrial DNA-enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity. JCI Insight. 2017;2:92634. https://doi.org/10.1172/jci.insight.92634.CrossRefPubMedGoogle Scholar
- 15.Saha B, Momen-Heravi F, Furi I, Kodys K, Catalano D, Gangopadhyay A, Haraszti R, Satishchandran A, Iracheta-Vellve A, Adejumo A, et al. Extracellular vesicles from mice with alcoholic liver disease carry a distinct protein cargo and induce macrophage activation via Hsp90. Hepatology. 2017;67(5):1986–2000. https://doi.org/10.1002/hep.29732.CrossRefGoogle Scholar
- 19.Momen-Heravi F, Saha B, Kodys K, Catalano D, Satishchandran A, Szabo G. Increased number of circulating exosomes and their microRNA cargos are potential novel biomarkers in alcoholic hepatitis. J Transl Med. 2015;13:261. https://doi.org/10.1186/s12967-015-0623-9.CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Povero D, Eguchi A, Li H, Johnson CD, Papouchado BG, Wree A, Messer K, Feldstein AE. Circulating extracellular vesicles with specific proteome and liver microRNAs are potential biomarkers for liver injury in experimental fatty liver disease. PLoS One. 2014;9:e113651. https://doi.org/10.1371/journal.pone.0113651.CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Garcia-Martinez I, Santoro N, Chen Y, Hoque R, Ouyang X, Caprio S, Shlomchik MJ, Coffman RL, Candia A, Mehal WZ. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest. 2016;126:859–64. https://doi.org/10.1172/JCI83885.CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Povero D, Eguchi A, Niesman IR, Andronikou N, de Mollerat du Jeu X, Mulya A, Berk M, Lazic M, Thapaliya S, Parola M, et al. Lipid-induced toxicity stimulates hepatocytes to release angiogenic microparticles that require Vanin-1 for uptake by endothelial cells. Sci Signal. 2013;6:ra88. https://doi.org/10.1126/scisignal.2004512.CrossRefPubMedPubMedCentralGoogle Scholar