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

作者：Tunda Hidvegi, Michael Ewing, Pamela Hale, Christine Dippold, Caroline S. Beckett, Carolyn Kemp, N.M. Maurice, Amitava Mukherjee, Christina Goldbach, Simon C. Watkins, George K. Michalopoulos, David H. Perlmutter · 发表于：Science · 年份：2010 · DOI：10.1126/science.1190354 · 被引用次数：604 · 研究领域：Autophagy in Disease and Therapy、Adenosine and Purinergic Signaling、Studies on Chitinases and Chitosanases

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.