An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis.
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.
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Tunda
T
Hidvegi
Michael
M
Ewing
Pamela
P
Hale
Christine
C
Dippold
Caroline
C
Beckett
Carolyn
C
Kemp
Nicholas
N
Maurice
Amitava
A
Mukherjee
Christina
C
Goldbach
Simon
S
Watkins
George
G
Michalopoulos
David H
DH
Perlmutter
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002220:Carbamazepine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects / Q000648:ultrastructure; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D012995:Solubility; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications / Q000378:metabolism* / Q000473:pathology
D050505:Mutant Proteins; D000515:alpha 1-Antitrypsin; D002220:Carbamazepine; D046988:Proteasome Endopeptidase Complex