| 摘要 |
The invention presented herein provides mice genetically modified in the transcription factor HNF4a and methods of using the mice as in vivo models. The a1 and a7 isoforms of HNF4a 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 HNF4a1, which possesses the AF-1 motif, and the second, P2, gives rise to HNF4a7, which does not. Modifying the HNF4a locus in the mouse genome, using murine embryonic stem cells that were injected in the early mouse embryo, produced mice that express either the al or the a7 isoform. The mice expressing exclusively HNF4a7 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 HNF4a1 exclusively has an altered pancreatic response to glucose injection, and a diabetes mellitus-like phenotype. |
