title: Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde.
abstract: Alcohol consumption exacerbates hepatitis C virus (HCV) pathogenesis and promotes disease progression, although the mechanisms are not quite clear. We have previously observed that acetaldehyde (Ach) continuously produced by the acetaldehyde-generating system (AGS), temporarily enhanced HCV RNA levels, followed by a decrease to normal or lower levels, which corresponded to apoptosis induction. Here, we studied whether Ach-induced apoptosis caused depletion of HCV-infected cells and what role apoptotic bodies (AB) play in HCV-alcohol crosstalk. In liver cells exposed to AGS, we observed the induction of miR-122 and miR-34a. As miR-34a has been associated with apoptotic signaling and miR-122 with HCV replication, these findings may suggest that cells with intensive viral replication undergo apoptosis. Furthermore, when AGS-induced apoptosis was blocked by a pan-caspase inhibitor, the expression of HCV RNA was not changed. AB from HCV-infected cells contained HCV core protein and the assembled HCV particle that infect intact hepatocytes, thereby promoting the spread of infection. In addition, AB are captured by macrophages to switch their cytokine profile to the proinflammatory one. Macrophages exposed to HCV(+) AB expressed more IL-1β, IL-18, IL-6, and IL-10 mRNAs compared with those exposed to HCV(-) AB. The generation of AB from AGS-treated HCV-infected cells even enhanced the induction of aforementioned cytokines. We conclude that HCV and alcohol metabolites trigger the formation of AB containing HCV particles. The consequent spread of HCV to neighboring hepatocytes via infected AB, as well as the induction of liver inflammation by AB-mediated macrophage activation potentially exacerbate the HCV infection course by alcohol and worsen disease progression.
authors.affiliation: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Murali
authors.initials: M
authors.lastname: Ganesan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Sathish Kumar
authors.initials: SK
authors.lastname: Natarajan
authors.affiliation: School of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska; and.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Justin L
authors.initials: JL
authors.lastname: Mott
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, Omaha, Nebraska.
authors.forename: Larisa I
authors.initials: LI
authors.lastname: Poluektova
authors.affiliation: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Benita L
authors.initials: BL
authors.lastname: McVicker
authors.affiliation: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Kusum K
authors.initials: KK
authors.lastname: Kharbanda
authors.affiliation: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Tuma
authors.affiliation: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; nosna@unmc.edu.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Osna
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism*; D017209:Apoptosis; D002460:Cell Line; D002478:Cells, Cultured; D016174:Hepacivirus / Q000472:pathogenicity / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism* / Q000821:virology; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: D007378:Interleukins; C531907:MIRN122 microRNA, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D012367:RNA, Viral; D014764:Viral Proteins; D000079:Acetaldehyde
keywords: HCV RNA; acetaldehyde; apoptosis; hepatocytes; macrophages