In this study, 1) we developed a comprehensive and functional human hepatic tissue in a mouse host, achieving a cellular composition and a tissue architecture similar to that of the human liver, 2) we leveraged this technology to model common human liver diseases and also obtain proof-of-concept evidence that key metabolic functions of human hepatocytes are not cell-autonomous, but rather controlled by NPCs, 3) we revealed a human-specific paracrine mechanism whereby human endothelial WNT2 controls cholesterol uptake and bile acid conjugation in human hepatocytes through receptor FZD5. This evidence concerns the gene FZD5 and liver disorder.