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 Idasanutlin 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 ICG-001 ic50 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. (HEPATOLOGY 2011;) Nonalcoholic fatty liver disease is the most rapidly increasing cause of liver disease in the western world.1 The spectrum of nonalcoholic fatty liver disease spans from steatosis to nonalcoholic steatohepatitis (NASH), which can lead to cirrhosis and hepatocellular cancer.1 Although the factors determining progression of NASH are yet Thalidomide to be fully defined, the clinical importance of increased susceptibility of the fatty liver to ischemia,2 bacterial lipopolysaccharide (LPS),3 viral infections,1 and drug-induced liver damage4 is emerging. Comorbidity of NASH with viral infections caused by RNA viruses, such as hepatitis C and human immunodeficiency virus (HIV) remains a clinical challenge.1 Hepatitis C virus (HCV)-infected patients with significant steatosis or superimposed NASH have rapid progression of liver disease, increased rate of fibrosis, and a decreased likelihood of sustained virological response to standard antiviral therapy.5 In HIV infection, highly active antiretroviral therapy induces extensive alterations to liver lipid metabolism, including liver damage and even liver failure.