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

作者：Hidvegi Tunda; Ewing Michael; Hale Pamela; Dippold Christine; Beckett Caroline; Kemp Carolyn; Maurice Nicholas; Mukherjee Amitava; Goldbach Christina; Watkins Simon; Michalopoulos George; Perlmutter David H^*

来源：Science, 2010, 329(5988): 229-232.

DOI：10.1126/science.1190354

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.

• 出版日期2010-7-9