A humanized mouse model of APOB deficiency recapitulates hypobetalipoproteinemia

Lipoprotein metabolism is significantly different between mice and humans thus making it difficult to model disorders of human lipid metabolism in transgenic mice. Systemic lipoprotein metabolism is predominantly governed by hepatocytes, and mice with humanized livers display human-like lipid profiles. Here we report a highly efficient method to knock out genes in human hepatocytes while retaining their ability to repopulate immune-deficient rodents. As proof-of-principle, Fah-deficient, immune-compromised mice were repopulated with Apolipoprotein B (APOB) knockout human hepatocytes. Mice humanized with knockout cells recapitulated typical features of human hypobetalipoproteinemia. We conclude that that human genetic disorders of lipid metabolism can be accurately modeled in a chimeric liver mouse by utilizing human knockout hepatocytes.