Human iPSC-hepatocyte modeling of alpha-1 antitrypsin heterozygosity reveals metabolic dysregulation and cellular heterogeneity

Individuals homozygous for the Zmutation in alpha-1 antitrypsin deficiency are known to be at increased risk for liver disease. It has also become clear that some degree of risk is similarly conferred by the hetero-zygous state. A lack of model systems that recapitulate heterozygosity in human hepatocytes has limited the ability to study the impact of a single Z alpha-1 antitrypsin (ZAAT) allele on hepatocyte biology. Here, we describe the derivation of syngeneic induced pluripotent stem cells (iPSCs) engineered to determine the effects of ZAAT heterozygosity in iPSC-hepatocytes (iHeps). We find that heterozygous MZ iHeps exhibit an intermediate disease phenotype and share with ZZ iHeps alterations in AAT protein processing and downstream perturbations including altered endoplasmic reticulum (ER) and mitochondrial morphology, reduced mitochondrial respiration, and branch-specific activation of the unfolded protein response in cell subpopulations. Our model of MZ heterozygosity thus provides evidence that a single Z allele is sufficient to disrupt hepatocyte homeostatic function.

Automated summary

Individuals homozygous for the Zmutation in alpha-1 antitrypsin deficiency are at increased risk for liver disease. Heterozygous individuals also have a degree of risk. Lack of model systems has limited the study of the impact of a single Z alpha-1 antitrypsin (ZAAT) allele on hepatocyte biology. This study successfully derived syngeneic induced pluripotent stem cells (iPSCs) to investigate the effects of ZAAT heterozygosity in iPSC-hepatocytes (iHeps), finding that MZ heterozygous iHeps exhibit an intermediate disease phenotype and share certain alterations with ZZ iHeps.