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An Autophagy-Enhancing Drug Promotes Degradation of Mutant α₁-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 and David H. Perlmutter
Science
New Series, Vol. 329, No. 5988 (9 July 2010), pp. 229-232
Stable URL: http://www.jstor.org/stable/40731949
Page Count: 4
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Abstract

In the classical form of αⁱ-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 αⁱ-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-enhandng 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 defidency and also provide a proof of principle for therapeutic use of autophagy enhancers.

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