title: Extracellular vesicles released by hepatocytes from gastric infusion model of alcoholic liver disease contain a MicroRNA barcode that can be detected in blood.
abstract: Extracellular vesicles (EVs) released during cell stress, or demise, can contain a barcode of the cell origin, including specific microRNAs (miRNAs). Here, we tested the hypothesis that during early alcoholic steatohepatitis (ASH) development, hepatocytes (HCs) release EVs with an miRNA signature that can be measured in circulation. A time-course experiment showed that after 2 weeks of intragastric infusion, a time point that results in isolated steatosis, there was no increase of blood EVs. After 4 weeks of infusion, mice developed features of early ASH accompanied by a marked increase in the level of EVs in blood (P < 0.05), as well as in culture media of isolated HCs (P < 0.001) and hepatic macrophages (P < 0.001), with HCs being the predominant source of EVs. The transcriptome analysis of HC-EVs from ASH mice detected differentially expressed miRNAs, including nine significantly up-regulated and four significantly down-regulated miRNAs. Target prediction and pathway analyses of the up-regulated miRNAs identified 121 potential target genes involved in inflammatory and cancer pathways, such as nuclear factor kappa B, EGF, Wnt, and B-cell lymphoma 2. Three miRNAs, let7f, miR-29a, and miR-340, were increased in blood EVs from ASH mice (P < 0.05), but not in blood EVs from three other models of chronic liver injury, including bile duct ligation, nonalcoholic steatohepatitis, and obese mice, as well as EVs released from hepatocytes exposed to ethanol. Blood EV level (P < 0.01) and three miRNAs (P < 0.05) were significantly increased in patients with ambulatory mild ALD as compared to nonalcoholics.
  
  
  
  Damaged hepatocytes from ASH mice are a key EV source with a specific miRNA cargo, which are specific for ASH-related liver injury. These findings uncover EVs as a potentially novel diagnostic for ASH. (Hepatology 2017;65:475-490).
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Eguchi
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis and Departments of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA.
authors.forename: Raul G
authors.initials: RG
authors.lastname: Lazaro
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis and Departments of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA.
authors.forename: Jiaohong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biomedical Informatics, University of California San Diego, La Jolla, CA.
authors.forename: Jihoon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA.
authors.forename: Davide
authors.initials: D
authors.lastname: Povero
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Willliams
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA.|Department of Medicine, VA San Diego Healthcare System, San Diego, CA.
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Ho
authors.affiliation: St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Stärkel
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA.|Department of Medicine, VA San Diego Healthcare System, San Diego, CA.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schnabl
authors.affiliation: Department of Biomedical Informatics, University of California San Diego, La Jolla, CA.
authors.forename: Lucila
authors.initials: L
authors.lastname: Ohno-Machado
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis and Departments of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA.|Department of Veterans Affairs, Greater Los Angeles Healthcare System, Los Angeles, CA.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA.
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000067128:Extracellular Vesicles / Q000378:metabolism*; D005235:Fatty Liver, Alcoholic / Q000378:metabolism* / Q000473:pathology*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012494:Sampling Studies; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D035683:MicroRNAs