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, David H. Perlmutter

Research output: Contribution to journalArticlepeer-review

463 Scopus citations

Abstract

In the classical form of α1-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 α1-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.

Original languageEnglish
Pages (from-to)229-232
Number of pages4
JournalScience
Volume329
Issue number5988
DOIs
StatePublished - Jul 9 2010

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