Autophagy-Enhancing Drug Promotes Degradation of Mutant α₁-Antitrypsin Z and Reduces Hepatic Fibrosis

• Published in: Science (American Association for the Advancement of Science) Vol. 329; no. 5988; pp. 229 - 232
• Main Authors: Hidvegi, Tunda, Ewing, Michael, Hale, Pamela, Dippold, Christine, Beckett, Caroline, Kemp, Carolyn, Maurice, Nicholas, Mukherjee, Amitava, Goldbach, Christina, Watkins, Simon, Michalopoulos, George, Perlmutter, David H
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 09.07.2010
• Subjects: animal models; autophagy; Biological and medical sciences; blood serum; carcinogenesis; Cell aggregates; Cell lines; Digestive system; Dosage; drugs; Fibrosis; Globules; glycoproteins; Hepatocytes; Liver; Liver cells; Liver diseases; Medical sciences; mutants; patients; Pharmacology. Drug treatments; point mutation; Secretion; testing; Hepatic fibrosis; Rodentia; Hepatic disease; Anticonvulsant; Tricyclic compound; Autophagy; Carcinogenesis; Carbamazepine; α1-Antitrypsin; Vertebrata; Mammalia; Mouse; Mood stabilizer; Animal; Carboxamide; Digestive diseases; Mutation; Mechanism of action; Dibenzazepine derivatives
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1190354

In the classical form of α₁-antitrypsin (AT) deficiency, a point mutation in AT alters the folding of a liver-derived secretory glycoprotein and renders it aggregation-prone. In addition to decreased serum concentrations of AT, the disorder is characterized by accumulation of the mutant α1-antitrypsin Z (ATZ) variant inside cells, causing hepatic fibrosis and/or carcinogenesis by a gain-of-toxic function mechanism. The proteasomal and autophagic pathways are known to mediate degradation of ATZ. Here we show that the autophagy-enhancing drug carbamazepine (CBZ) decreased the hepatic load of ATZ and hepatic fibrosis in a mouse model of AT deficiency-associated liver disease. These results provide a basis for testing CBZ, which has an extensive clinical safety profile, in patients with AT deficiency and also provide a proof of principle for therapeutic use of autophagy enhancers.