An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis - PubMed (original) (raw)

. 2010 Jul 9;329(5988):229-32.

doi: 10.1126/science.1190354. Epub 2010 Jun 3.

Michael Ewing, Pamela Hale, Christine Dippold, Caroline Beckett, Carolyn Kemp, Nicholas Maurice, Amitava Mukherjee, Christina Goldbach, Simon Watkins, George Michalopoulos, David H Perlmutter

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An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis

Tunda Hidvegi et al. Science. 2010.

Abstract

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.

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