Capitalizing on the autophagic response for treatment of liver disease caused by alpha-1-antitrypsin deficiency and other genetic diseases

Biomed Res Int. 2014;2014:459823. doi: 10.1155/2014/459823. Epub 2014 Jun 3.


Alpha-1-antitrypsin deficiency (ATD) is one of the most common genetic causes of liver disease and is a prototype of liver diseases caused by the pathologic accumulation of aggregated mutant alpha-1-antitrypsin Z (ATZ) within liver cells. In the case of ATD-associated liver disease, the resulting "gain-of-function" toxicity can lead to serious clinical manifestations, including cirrhosis and hepatocellular carcinoma. Currently, the only definitive therapy for ATD-associated liver disease is liver transplantation, but recent efforts have demonstrated the exciting potential for novel therapies that target disposal of the mutant protein aggregates by harnessing a cellular homeostasis mechanism called autophagy. In this review, we will summarize research advances on autophagy and genetic liver diseases. We will discuss autophagy enhancer strategies for liver disease due to ATD and another genetic liver disease, inherited hypofibrinogenemia, caused by the proteotoxic effects of a misfolded protein. On the basis of recent evidence that autophagy plays a role in cellular lipid degradation, we also speculate about autophagy enhancer strategies for treatment of hepatic lipid storage diseases such as cholesterol ester storage disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Autophagy / genetics*
  • Cholesterol Ester Storage Disease / genetics
  • Cholesterol Ester Storage Disease / therapy
  • Genetic Therapy*
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • alpha 1-Antitrypsin / genetics*
  • alpha 1-Antitrypsin Deficiency / genetics*
  • alpha 1-Antitrypsin Deficiency / pathology
  • alpha 1-Antitrypsin Deficiency / therapy


  • alpha 1-Antitrypsin

Supplementary concepts

  • alpha-1-Antitrypsin Deficiency, Autosomal Recessive