Mitochondrial antiviral signaling protein defect links impaired antiviral response and liver injury in steatohepatitis in mice
Authors
Csak, TimeaDolganiuc, Angela
Kodys, Karen
Nath, Bharath D.
Petrasek, Jan
Bala, Shashi
Lippai, Dora
Szabo, Gyongyi
UMass Chan Affiliations
Department of Medicine, Division of GastroenterologyDocument Type
Journal ArticlePublication Date
2011-06-01Keywords
Adaptor Proteins, Signal TransducingAnimals
Apoptosis
Biopsy
Choline Deficiency
Cytokines
Disease Models, Animal
Fatty Liver
Female
Humans
Interferon Type I
Liver
Methionine
Mice
Mice, Inbred C57BL
Mitochondria, Liver
Poly I-C
RNA, Double-Stranded
Receptor-Interacting Protein Serine-Threonine Kinases
Digestive System Diseases
Gastroenterology
Immunology and Infectious Disease
Virus Diseases
Metadata
Show full item recordAbstract
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.Source
Hepatology. 2011 Jun;53(6):1917-31. doi: 10.1002/hep.24301. Epub 2011 May 2. Link to article on publisher's site
DOI
10.1002/hep.24301Permanent Link to this Item
http://hdl.handle.net/20.500.14038/31064PubMed ID
21425308Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1002/hep.24301