Hepatocyte Nuclear Factor 4 Alpha – New Insights into an Old Receptor

Hepatocyte nuclear factor 4 alpha (HNF4A) was identified more than three decades ago as a liver-specific DNA binding activity in nuclear extracts. When its cDNA was cloned a couple of years later its predicted amino acid sequence earned it membership into the emerging family of ligand-dependent nuclear receptors (NR). Currently, HNF4A is considered to be the master regulator of liver-specific transcription, playing a role in hemophilia, atherosclerosis, hepatitis, hepatocellular carcinoma and chronic liver failure. MODY1 mutations in the human HNF4A gene reveal a critical yet ill-defined role for this important transcription factor in diabetes, while other mutations classify HNF4A as an Inflammatory Bowel Disease (IBD) susceptibility gene. Recent studies reveal a critical role for HNF4A in colon cancer as well as intriguing interactions with the gut microbiome. Originally classified as an orphan receptor, various fatty acids were subsequently found in the HNF4A ligand binding pocket. However, the role of those ligands remains obscure, frustrating attempts to develop it into a viable drug target like so many other members of the NR superfamily. Evolutionary biology studies reveal ancient origins for HNF4A, including as a potential founder of the NR family in metazoans.

This Research Topic will focus on our current understanding of HNF4a, one of the most highly expressed transcription factors in the digestive tract and yet one of the most overlooked, presumably due to the ambiguous status of its ligand. The special topic will cover what we have learned about HNF4A from model organisms such as C. elegans, zebrafish and Drosophila, including its role in the evolution of NRs and aging. The topic will cover recent developments in our understanding of the role of HNF4A in fatty acid and glucose metabolism as well as its role in regulating the cell cycle and cancer, its interaction with the gut microbiome and the function of its ligand as well as its various isoforms. Updates on the role of HNF4A in diseases such as diabetes, fatty liver disease and cirrhosis, cancer and colitis will be covered as well as new findings from unbiased, omics-approaches.

We have identified more than 20 active researchers in the field of HNF4A who have published primary research recently on one of the topics above and/or who could provide a historical perspective. We propose to contact those authors and invite them to submit primary research papers from their labs and/or mini review articles on HNF4A.

The goal of this topic is to synthesize what is known about this important regulator of gene expression and thereby shed new light on our understanding of metabolism, cell proliferation and disease in general.