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Science 329 (5988): 229-232

Copyright © 2010 by the American Association for the Advancement of Science

An Autophagy-Enhancing Drug Promotes Degradation of Mutant {alpha}1-Antitrypsin Z and Reduces Hepatic Fibrosis

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*

Abstract: In the classical form of {alpha}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 concentrations of AT, the disorder is characterized by accumulation of the mutant {alpha}1-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.

Departments of Pediatrics, Pathology, Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA.

* To whom correspondence should be addressed. E-mail: david.perlmutter{at}chp.edu

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