Mitochondrial antiviral signaling protein defect links impaired antiviral response and liver injury in steatohepatitis in mice

Timea Csak, Angela Dolganiuc, Karen Kodys, Bharath Nath, Jan Petrasek, Shashi Bala, Dora Lippai, G. Szabó

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Abstract

Mitochondrial dysfunction is a pathogenic feature of nonalcoholic steatohepatitis (NASH). NASH complicates hepatotropic viral disease. The mitochondrial antiviral signaling protein (MAVS) is the adapter of helicase receptors involved in sensing double-stranded RNA (dsRNA). We hypothesized that impaired MAVS function may contribute to insufficient antiviral response and liver damage in steatohepatitis. We identified reduced MAVS protein levels and increased MAVS association with the proteasome subunit alpha type 7 (PSMA7) in livers from mice given a methionine-choline-deficient (MCD) diet. Decreased association of MAVS with mitochondria and increased cytosolic cytochrome c indicated mitochondrial damage in steatohepatitis. In vivo administration of the synthetic dsRNA polyinosinic:polycytidylic acid [poly(I:C)], but not lipopolysaccharide or cytidine-phosphate-guanosine-rich DNA, resulted in impaired induction of type I interferons (IFNs) and proinflammatory cytokines in steatohepatitis. Consistent with a defect in helicase receptor-induced signaling, there was loss of poly(I:C)-induced translocation of MAVS to the cytosol and decreased IFN regulatory factor 3 phosphorylation. Caspases 1 and 8, both of which cleave MAVS, were increased in MCD diet-fed mice. At baseline, steatohepatitis was associated with increased serum alanine aminotransferase (ALT), apoptosis and caspase 3 activation compared with controls. In contrast to apoptosis in controls, necrosis was induced by poly(I:C) stimulation in steatohepatitis. Hepatocyte necrosis was indicated by elevated serum high-mobility group box protein-1 and ALT and was correlated with increased expression of receptor-interacting protein 3 (RIP3), a master regulator of necrosis. Increased expression of MAVS, PSMA7, and RIP3 messenger RNA was also present in human NASH livers. Conclusion: Our novel findings suggest that mitochondrial damage in steatohepatitis extends to MAVS, an adapter of helicase receptors, resulting in inefficient type I IFN and inflammatory cytokine response but increased hepatocyte necrosis and RIP3 induction in response to a dsRNA viral challenge. These mechanisms may contribute to progressive liver damage and impaired viral clearance in NASH.

Original languageEnglish
Pages (from-to)1917-1931
Number of pages15
JournalHepatology
Volume53
Issue number6
DOIs
Publication statusPublished - Jun 2011

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Fatty Liver
Antiviral Agents
Liver
Wounds and Injuries
Receptor-Interacting Protein Serine-Threonine Kinases
Poly I-C
Proteins
Double-Stranded RNA
Necrosis
Interferon Type I
Proteasome Endopeptidase Complex
Choline
Alanine Transaminase
Methionine
Hepatocytes
Cytosine Nucleotides
Interferon Regulatory Factor-3
link protein
Apoptosis
Cytokines

ASJC Scopus subject areas

  • Hepatology

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Mitochondrial antiviral signaling protein defect links impaired antiviral response and liver injury in steatohepatitis in mice. / Csak, Timea; Dolganiuc, Angela; Kodys, Karen; Nath, Bharath; Petrasek, Jan; Bala, Shashi; Lippai, Dora; Szabó, G.

In: Hepatology, Vol. 53, No. 6, 06.2011, p. 1917-1931.

Research output: Contribution to journalArticle

Csak, Timea ; Dolganiuc, Angela ; Kodys, Karen ; Nath, Bharath ; Petrasek, Jan ; Bala, Shashi ; Lippai, Dora ; Szabó, G. / Mitochondrial antiviral signaling protein defect links impaired antiviral response and liver injury in steatohepatitis in mice. In: Hepatology. 2011 ; Vol. 53, No. 6. pp. 1917-1931.
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abstract = "Mitochondrial dysfunction is a pathogenic feature of nonalcoholic steatohepatitis (NASH). NASH complicates hepatotropic viral disease. The mitochondrial antiviral signaling protein (MAVS) is the adapter of helicase receptors involved in sensing double-stranded RNA (dsRNA). We hypothesized that impaired MAVS function may contribute to insufficient antiviral response and liver damage in steatohepatitis. We identified reduced MAVS protein levels and increased MAVS association with the proteasome subunit alpha type 7 (PSMA7) in livers from mice given a methionine-choline-deficient (MCD) diet. Decreased association of MAVS with mitochondria and increased cytosolic cytochrome c indicated mitochondrial damage in steatohepatitis. In vivo administration of the synthetic dsRNA polyinosinic:polycytidylic acid [poly(I:C)], but not lipopolysaccharide or cytidine-phosphate-guanosine-rich DNA, resulted in impaired induction of type I interferons (IFNs) and proinflammatory cytokines in steatohepatitis. Consistent with a defect in helicase receptor-induced signaling, there was loss of poly(I:C)-induced translocation of MAVS to the cytosol and decreased IFN regulatory factor 3 phosphorylation. Caspases 1 and 8, both of which cleave MAVS, were increased in MCD diet-fed mice. At baseline, steatohepatitis was associated with increased serum alanine aminotransferase (ALT), apoptosis and caspase 3 activation compared with controls. In contrast to apoptosis in controls, necrosis was induced by poly(I:C) stimulation in steatohepatitis. Hepatocyte necrosis was indicated by elevated serum high-mobility group box protein-1 and ALT and was correlated with increased expression of receptor-interacting protein 3 (RIP3), a master regulator of necrosis. Increased expression of MAVS, PSMA7, and RIP3 messenger RNA was also present in human NASH livers. Conclusion: Our novel findings suggest that mitochondrial damage in steatohepatitis extends to MAVS, an adapter of helicase receptors, resulting in inefficient type I IFN and inflammatory cytokine response but increased hepatocyte necrosis and RIP3 induction in response to a dsRNA viral challenge. These mechanisms may contribute to progressive liver damage and impaired viral clearance in NASH.",
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AU - Szabó, G.

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