The genetics of primary biliary cirrhosis: The revolution moves on

✍ Scribed by David E. J. Jones; George Mells

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 237 KB
• Volume: 53
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.24096

✦ Synopsis

In the classical form of alpha1-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 alpha1-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.