Molecular mechanism of hepatocellular injury in alpha 1 antitrypsin deficiency

Abstract

Liver injury in PiZZ Α 1 -antitrypsin (Α 1 -AT) deficiency probably results from toxic effects of the abnormal Α 1 -AT molecule accumulating within the ER of liver cells. However, only 12–15% of individuals with this same genotype develops liver disease. Therefore, we predicted that other genetic traits that determine the net intracellular accumulation of the mutant Α 1 -AT molecule would also determine susceptibility to liver disease. To address this prediction, we transduced skin fibroblasts from PiZZ individuals with liver disease or without liver disease with amphotropic recombinant retroviral particles designed for constitutive expression of the mutant Α 1 -AT Z gene. Human skin fibroblasts do not express the endogenous Α 1 -AT gene but presumably express other genes involved in postsynthetic processing of secretory proteins. The results show that expression of human Α 1 -AT M gene was conferred on each fibroblast cell line. Compared to the same cell line transduced with the wild-type Α 1 -AT M gene, there was selective intracellular accumulation of the mutant Α 1 -AT Z protein in each case. However, there was a marked delay in degradation of the mutant Α 1 -AT Z protein after it accumulated in the fibroblasts from ZZ individuals with liver disease (“susceptible hosts”) as compared to those without liver disease (“protected hosts”). Appropriate disease controls showed that the lag in degradation in susceptible hosts is specific for the combination of PiZZ phenotype and liver disease. Biochemical characteristics of Α 1 -AT Z degradation in the protected hosts were found to be similar to those of a common ER degradation pathway previously described in model experimental cell systems for T-cell receptor Α subunits and asialoglycoprotein receptor subunits, therefore, raising the possibility that the lag in degradation in the susceptible host is a defect in this common ER degradation pathway. Thus, these data provide evidence that other genetic traits that affect the fate of the abnormal Α 1 -AT Z molecule, at least in part, determine susceptibility to liver disease. These data also validate a system for elucidating the biochemical/genetic characteristics of these traits and for examining the relevance to human disease of pathways for protein dÉradation in the ER.