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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Autophagy / drug effects*
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Carbamazepine / administration & dosage
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Carbamazepine / pharmacology*
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Carbamazepine / therapeutic use
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Cell Line
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Disease Models, Animal
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Endoplasmic Reticulum / metabolism
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HeLa Cells
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Humans
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Liver / drug effects
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Liver / metabolism*
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Liver / pathology
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Liver Cirrhosis / drug therapy*
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Liver Cirrhosis / etiology
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Liver Cirrhosis / metabolism
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Liver Cirrhosis / pathology
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Mice
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Mice, Transgenic
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Mutant Proteins / chemistry
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Mutant Proteins / metabolism
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Phagosomes / drug effects
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Phagosomes / ultrastructure
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Phenotype
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Proteasome Endopeptidase Complex / metabolism
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Protein Folding
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Solubility
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alpha 1-Antitrypsin / chemistry
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alpha 1-Antitrypsin / genetics
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alpha 1-Antitrypsin / metabolism*
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alpha 1-Antitrypsin Deficiency / complications
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alpha 1-Antitrypsin Deficiency / metabolism*
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alpha 1-Antitrypsin Deficiency / pathology
Substances
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Mutant Proteins
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alpha 1-Antitrypsin
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Carbamazepine
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Proteasome Endopeptidase Complex