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dc.contributor.authorCsak, Timea
dc.contributor.authorDolganiuc, Angela
dc.contributor.authorKodys, Karen
dc.contributor.authorNath, Bharath D.
dc.contributor.authorPetrasek, Jan
dc.contributor.authorBala, Shashi
dc.contributor.authorLippai, Dora
dc.contributor.authorSzabo, Gyongyi
dc.date2022-08-11T08:08:36.000
dc.date.accessioned2022-08-23T16:01:12Z
dc.date.available2022-08-23T16:01:12Z
dc.date.issued2011-06-01
dc.date.submitted2012-10-10
dc.identifier.citation<p>Hepatology. 2011 Jun;53(6):1917-31. doi: 10.1002/hep.24301. Epub 2011 May 2. <a href="http://dx.doi.org/10.1002/hep.24301" target="_blank">Link to article on publisher's site</a></p>
dc.identifier.issn0270-9139 (Linking)
dc.identifier.doi10.1002/hep.24301
dc.identifier.pmid21425308
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31064
dc.description.abstractMitochondrial 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=21425308&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253554/pdf/nihms280549.pdf
dc.subjectAdaptor Proteins, Signal Transducing
dc.subjectAnimals
dc.subjectApoptosis
dc.subjectBiopsy
dc.subjectCholine Deficiency
dc.subjectCytokines
dc.subjectDisease Models, Animal
dc.subjectFatty Liver
dc.subjectFemale
dc.subjectHumans
dc.subjectInterferon Type I
dc.subjectLiver
dc.subjectMethionine
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMitochondria, Liver
dc.subjectPoly I-C
dc.subjectRNA, Double-Stranded
dc.subjectReceptor-Interacting Protein Serine-Threonine Kinases
dc.subjectDigestive System Diseases
dc.subjectGastroenterology
dc.subjectImmunology and Infectious Disease
dc.subjectVirus Diseases
dc.titleMitochondrial antiviral signaling protein defect links impaired antiviral response and liver injury in steatohepatitis in mice
dc.typeJournal Article
dc.source.journaltitleHepatology (Baltimore, Md.)
dc.source.volume53
dc.source.issue6
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gastroenterology_pp/121
dc.identifier.contextkey3383619
html.description.abstract<p>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.</p> <p>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.</p>
dc.identifier.submissionpathgastroenterology_pp/121
dc.contributor.departmentDepartment of Medicine, Division of Gastroenterology
dc.source.pages1917-31


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