Authors:
Tunda Hidvegi, Michael Ewing, Pamela Hale, Christine Dippold, Caroline Beckett Carolyn Kemp, Nicholas Maurice, Amitava Mukherjee, Christina Goldbach, Simon Watkins, George Michalopoulos, & David H. Perlmutter
Summary:
In the classical form of 1-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 levels of AT, the disorder is characterized by accumulation of the mutant 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-in-principle for therapeutic use of autophagy enhancers.
Source:
Science; (06/03/10)