Alpha-1-antitrypsin deficiency: Importance of proteasomal and autophagic degradative pathways in disposal of liver diseaseassociated protein aggregates

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Abstract

Alpha-1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children. The primary pathological issue is a point mutation that renders an abundant hepatic secretory glycoprotein prone to altered folding and a tendency to polymerize and aggregate. However, the expression of serious liver damage among homozygotes is dependent on genetic andor environmental modifiers. Several studies have validated the concept that endogenous hepatic pathways for disposal of aggregation-prone proteins, including the proteasomal and autophagic degradative pathways, could play a key role in the variation in hepatic damage and be the target of the modifiers. Exciting recent results have shown that a drug that enhances autophagy can reduce the hepatic load of aggregated protein and reverse fibrosis in a mouse model of this disease.

Original languageEnglish
Pages (from-to)333-345
Number of pages13
JournalAnnual review of medicine
Volume62
DOIs
StatePublished - Feb 18 2011
Externally publishedYes

Keywords

  • aggregation-prone proteins
  • chronic hepatitis
  • cirrhosis
  • hepatocellular carcinoma
  • misfolded proteins

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