Normalization of the enterohepatic circulation in animals with a chimeric humanized liver

Abstract

Methods of normalizing bile acid production in a mouse engrafted with human hepatocytes by the administration of human FGF19 are disclosed. Also disclosed is a transgenic host animal, such as a mouse, that expresses human FGF19 that has normalized bile acid production when engrafted with human hepatocytes.

1 . A transgenic mouse comprising:
 a first genetic alteration that results in uPA overexpression and   a second genetic alteration that results in the expression of a protein of SEQ ID NO: 1; where the host animal has normalized bile acid production when engrafted with human hepatocytes and where the transgenic mouse is a SCID mouse.   
     
     
         2 . The transgenic mouse of  claim 1 , wherein expression of the protein of SEQ ID NO: 1 is driven by a human FGF19 promoter. 
     
     
         3 . The transgenic mouse of  claim 1 , further comprising an FGF19 enhancer. 
     
     
         4 . The transgenic mouse of  claim 3 , further comprising all FGF19 regulatory elements less than 75 kb 5′ of the human FGF19 gene on human chromosome 11 and/or further comprising all FGF19 regulatory elements less than 75 kb 3′ of the human FGF19 gene on human chromosome 11. 
     
     
         5 . The transgenic mouse of  claim 4  comprising BAC RP11-266K14.