NIAAA-supported researchers have discovered that extracellular vesicles (EVs) released by liver cells in a mouse model of alcoholic steatohepatitis (ASH) contain a micro ribonucleic acid (miRNA) signature detectable in the blood. ASH is a form of liver disease and the miRNA may serve as a “barcode” to help diagnose early-stage ASH in humans. EVs are small membrane structures that are released by active or damaged cells. EVs contain many different molecules, including miRNAs, which regulate cell responses and provide clues about the EV’s cell of origin.
In the study, researchers continuously administered ethanol to mice with incremental increases every two days. A control group received a liquid diet matched in caloric content with the alcohol group. At two weeks and four weeks, the researchers isolated and cultured hepatocytes (liver cells) and characterized the EVs released by these cells using standard laboratory techniques. After four weeks, the mice developed features of early-stage ASH and had increased levels of EVs in the blood compared to controls. Analysis of the miRNA suggests that hepatocytes were the primary source of these EVs.
Building on this research, the team analyzed the miRNA profiles of the EVs in the blood of the ASH mice and three other mouse models of chronic liver injury, as well as hepatocytes exposed directly to ethanol. They identified three miRNAs—let7f, mrR-29a, mrR-340—whose levels increased in the blood EVs of ASH mice, but not in the blood EVs of the other liver disease models. The researchers also conducted a small pilot study in humans with ambulatory mild alcoholic liver disease and found that the levels of EVs and miRNAs also had increased in these patients’ blood compared to individuals without alcoholic liver disease.
Nearly half of all liver disease deaths in the United States each year are attributed to alcohol misuse. Early detection of alcohol-induced liver disease is key to preventing progression to more serious disease. Taken together, these findings suggest that ASH-associated EVs and their miRNA “barcode” can be used to distinguish ASH from other types of liver disease, and potentially serve as novel biomarkers and therapeutic targets for ASH.
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Eguchi, A.; Lazaro, R.G.; Wang, J.; Kim, J.; Povero, D.; Willliams, B.; Ho, S.B.; Stärkel, P.; Schnabl, B.; Ohno-Machado, L.; Tsukamoto, H.; and Feldstein, A.E. Extracellular vesicles released by hepatocytes from gastric infusion model of alcoholic liver disease contain a MicroRNA barcode that can be detected in blood. Hepatology 65(2):475–490, 2017.