Activation of the c‐Jun N‐terminal kinase pathway aggravates proteotoxicity of hepatic mutant Z alpha1‐antitrypsin

• DOI: 10.1002/hep.29035
• Publication Date: 2017-01-10T23:03:22Z
• Authors: Nunzia Pastore; Sergio Attanasio; Barbara Granese; Raffaele Castello; Jeffrey Teckman; Andrew A. Wilson; Andrea Ballabio; Nicola Brunetti‐P...
• Keywords: c-jun; Pathogenesis; Liver disease

Alpha1-antitrypsin deficiency is a genetic disease that can affect both the lung and liver. The vast majority of patients harbor mutation in serine protease inhibitor 1A (SERPINA1) gene leading to single amino acid substitution results an unfolded protein prone polymerization. defciency-related liver therefore caused by gain-of-function mechanism due accumulation mutant Z alpha1-antitrypsin (ATZ) key example induced toxicity. Intracellular retention ATZ triggers complex injury cascade including apoptosis other mechanisms, although several aspects pathogenesis are still unclear. We show induces activation c-Jun N-terminal kinase (JNK) ablation JNK1 or JNK2 decreased levels vivo reducing c-Jun-mediated SERPINA1 expression. JNK was confirmed livers homozygous for allele, with severe requiring hepatic transplantation. Treatment patient-derived pluripotent stem cell-hepatic cells reduced ATZ.These data reveal pathway add new therapeutic entry points ATZ. (Hepatology 2017;65:1865-1874).