title: α1-antitrypsin deficiency and the hepatocytes - an elegans solution to drug discovery.
abstract: Hepatocytes are metabolically active cells of the liver that play an important role in the biosynthesis of proteins including α1-antitrypsin. Mutations in the α1-antitrypsin gene can lead to protein misfolding, polymerization/aggregation and retention of protein within the endoplasmic reticulum of hepatocytes. The intracellular accumulation of α1-antitrypsin aggregates can lead to liver disease and increased likelihood of developing hepatocellular carcinomas. Of note, only ~10% of individuals with α1-antitrypsin-deficiency develop severe liver disease suggesting that there are other genetic and/or environmental factors that determine disease outcome. The nematode, Caenorhabditis elegans, is a powerful genetic model organism to study molecular aspects of human disease. In this review, we discuss the functional similarities between the intestinal cells of C. elegans and human hepatocytes and how a C. elegans model of α1-antitrypsin-deficiency can be used as a tool for identifying genetic modifiers and small molecule drugs.
authors.affiliation: Department of Pediatrics, Cell Biology and Physiology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.
authors.forename: Linda P
authors.initials: LP
authors.lastname: O'Reilly
authors.affiliation: Department of Pediatrics, Cell Biology and Physiology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Perlmutter
authors.affiliation: Department of Pediatrics, Cell Biology and Physiology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Silverman
authors.affiliation: Department of Pediatrics, Cell Biology and Physiology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA. Electronic address: stephen.pak@chp.edu.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pak
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D004195:Disease Models, Animal; D055808:Drug Discovery; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D019896:alpha 1-Antitrypsin Deficiency / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*
keywords: C. elegans; Hepatocyte; Liver disease; Protein aggregation; α1-Antitrypsin deficiency