Gene regulation in rodent hepatocytes during development, differentiation and disease.

The expression of genes in the liver is mostly controlled at the transcriptional level and depends on the regulatory interactions between cis-acting sequences and trans-acting molecules. Proximal promoters and distant enhancers in combination with a number of hepatocyte-enriched DNA-binding proteins and general transcription factors interact specifically with these elements and control the expression of liver-specific genes. Hepatocyte-enriched regulatory proteins have been isolated from liver nuclear extracts, characterized, and their corresponding genes have been cloned. These include the hepatocyte nuclear factors 1, 3, 4 (HNF-1,3,4), some members of the CAAAT/enhancer binding protein (C/EBP) family, and D site binding protein (DBP). These factors belong to larger families and are able to form heterodimers, perhaps with the exception of the HNF-3 family, with other members of the same family. Interestingly, the majority of the genes encoding such proteins are themselves regulated at the transcriptional level, although both transcriptional and post-transcriptional events modulate their expression during development, hepatocyte differentiation and disease, suggesting that a transcriptional cascade may play a critical role in mammalian liver development and differentiation.