HNF4 & alpha; isoforms: the fraternal twin master regulators of liver function

In the more than 30 years since the purification and cloning of Hepatocyte Nuclear Factor 4 (HNF4a), considerable insight into its role in liver function has been gleaned from its target genes and mouse experiments. HNF4a plays a key role in lipid and glucose metabolism and intersects with not just diabetes and circadian rhythms but also with liver cancer, although much remains to be elucidated about those interactions. Similarly, while we are beginning to elucidate the role of the isoforms expressed from its two promoters, we know little about the alternatively spliced variants in other portions of the protein and their impact on the 1000-plus HNF4a target genes. This review will address how HNF4a came to be called the master regulator of liver-specific gene expression with a focus on its role in basic metabolism, the contributions of the various isoforms and the intriguing intersection with the circadian clock.

Automated summary

Since the purification and cloning of Hepatocyte Nuclear Factor 4 (HNF4a) more than 30 years ago, we have gained considerable insight into its role in liver function through its target genes and mouse experiments. HNF4a is a key player in lipid and glucose metabolism, and it intersects with diabetes, circadian rhythms, and liver cancer, although further research is needed to fully understand these interactions. While the isoforms expressed from its two promoters are being elucidated, little is known about the alternatively spliced variants in other regions of the protein and their impact on the 1000-plus HNF4a target genes.