Downregulation of HNF-4α and defective zonation in livers expressing mutant Z α1-antitrypsin

α1 -antitrypsin (AAT) deficiency is one of the most common genetic disorders and the liver disease due to the Z mutant of α1 -antitrypsin (ATZ) is a prototype of conformational disorder due to misfolding of protein with consequent aberrant intermolecular protein aggregation. In the present study, we found that livers of PiZ transgenic mice expressing the human ATZ have altered expression of a network of hepatocyte transcriptional factors including HNF4-α, that is early downregulated and induces a transcriptional repression of ATZ expression. Reduced HNF-4α was associated with activation of β-catenin that regulates liver zonation. Livers of PiZ mice and human patients with AAT deficiency were both found to have a severe perturbation of liver zonation. Functionally, PiZ mice showed a severe defect of ureagenesis, as shown by increased baseline ammonia, and reduced urea production and survival after an ammonia challenge. Downregulation of HNF-4α expression and defective zonation in livers have not been yet recognized as features of the liver disease caused by ATZ and are likely responsible for metabolic disturbances and for the increased risks of hepatocellular carcinoma in patients with AAT deficiency. In conclusion, these findings are consistent with the concept that abnormal AAT protein conformation and intrahepatic accumulation have broad effect on metabolic liver functions. This article is protected by copyright. All rights reserved.