TRANSGENIC HFN4α MICE EXPRESSING THERAPEUTIC TARGET AF1 DOMAINS AND THEIR METHODS OF USE AS MODELS FOR METABOLIC DISORDERS

摘要

The invention presented herein provides mice genetically modified in the transcription factor HNF4α and methods of using the mice as in vivo models. The α1 and α7 isoforms of HNF4α are distinguished by N-terminal amino acids encoded by the first exons, which comprise the AF-1 transactivation motif. These isoforms result from two alternative promoters. The first, P1, gives rise to HNF4α1, which possesses the AF-1 motif, and the second, P2, gives rise to HNF4α7, which does not. Modifying the HNF4α locus in the mouse genome, using murine embryonic stem cells that were injected in the early mouse embryo, produced mice that express either the αl or the α7 isoform. The mice expressing exclusively HNF4α7 have altered serum triglyceride and cholesterol levels and express low levels of CAR, another transcription factor, which is implicated in xenobiotic detoxification. A reciprocal transgenic mouse expressing HNF4α1 exclusively has an altered pancreatic response to glucose injection, and a diabetes mellitus-like phenotype.