An Autophagy-Enhancing Drug Promotes Degradation of Mutant α1-Antitrypsin Z and Reduces Hepatic Fibrosis

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Science  09 Jul 2010:
Vol. 329, Issue 5988, pp. 229-232
DOI: 10.1126/science.1190354

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Correcting a Liver Problem

The classical form of α1-antitrypsin (AT) deficiency is caused by a point mutation that alters the folding and causes intracellular aggregation of AT—an abundant liver-derived plasma glycoprotein. AT deficiency is the most common genetic cause of liver disease in childhood and can also lead to cirrhosis and/or hepatocellular carcinoma in adulthood. Carbamazepine is a drug known to be well tolerated in humans that enhances the intracellular degradation process known as autophagy. Now, Hidvegi et al. (p. 229, published online June 3; see the Perspective by Sifers) show that carbamazepine can reduce the severity of liver disease in a mouse model of AT deficiency by enhancing the degradation of misfolded accumulated AT.


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.

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