10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)G930-G940
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume310
Issue number11
DOIs
StatePublished - Jun 1 2016

Fingerprint

Acetaldehyde
Hepacivirus
Hepatocytes
Apoptosis
Alcohols
Virion
Disease Progression
Macrophages
RNA
Cytokines
Extracellular Vesicles
Interleukin-18
Caspase Inhibitors
Macrophage Activation
Liver
Virus Diseases
Virus Replication
Interleukin-1
Alcohol Drinking
Interleukin-10

Keywords

  • Acetaldehyde
  • Apoptosis
  • HCV RNA
  • Hepatocytes
  • Macrophages

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

@article{8d799835197c47fb956797248b2bba48,
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.",
keywords = "Acetaldehyde, Apoptosis, HCV RNA, Hepatocytes, Macrophages",
author = "Murali Ganesan and Natarajan, {Sathish K} and Jinjin Zhang and Mott, {Justin L} and Poluektova, {Larisa Y} and McVicker, {Benita L} and Kusum Kharbanda and Tuma, {Dean J.} and Osna, {Natalia A}",
year = "2016",
month = "6",
day = "1",
doi = "10.1152/ajpgi.00021.2016",
language = "English (US)",
volume = "310",
pages = "G930--G940",
journal = "American Journal of Physiology - Renal Physiology",
issn = "0363-6127",
publisher = "American Physiological Society",
number = "11",

}

TY - JOUR

T1 - Role of apoptotic hepatocytes in HCV dissemination

T2 - Regulation by acetaldehyde

AU - Ganesan, Murali

AU - Natarajan, Sathish K

AU - Zhang, Jinjin

AU - Mott, Justin L

AU - Poluektova, Larisa Y

AU - McVicker, Benita L

AU - Kharbanda, Kusum

AU - Tuma, Dean J.

AU - Osna, Natalia A

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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.

AB - 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.

KW - Acetaldehyde

KW - Apoptosis

KW - HCV RNA

KW - Hepatocytes

KW - Macrophages

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U2 - 10.1152/ajpgi.00021.2016

DO - 10.1152/ajpgi.00021.2016

M3 - Article

C2 - 27056722

AN - SCOPUS:84984598790

VL - 310

SP - G930-G940

JO - American Journal of Physiology - Renal Physiology

JF - American Journal of Physiology - Renal Physiology

SN - 0363-6127

IS - 11

ER -