HNF4α--role in drug metabolism and potential drug target?

Abstract

Hepatocyte nuclear factor 4α (HNF4α) is a highly conserved member of the nuclear receptor superfamily of ligand-dependent transcription factors. It is best known as a master regulator of liver-specific gene expression, especially those genes involved in lipid transport and glucose metabolism. However, there is also a growing body of work that indicates the importance of HNF4α in the regulation of genes involved in xenobiotic and drug metabolism. A recent study identifying the essential fatty acid linoleic acid (LA, C18:2) as the endogenous, reversible ligand for HNF4α suggests that HNF4α may also be a potential drug target and that its activity may be regulated by diet. This review will discuss the role of HNF4α in drug metabolism, including the genes it regulates, the factors that regulate its activity, and its potential as a drug target.

Figure 1. Central role of HNF4α in the regulation of Phase I and Phase II genes

Depicted are the NRs and liver-enriched transcription factors known to interact with HNF4α protein (an obligate homodimer) either physically and/or functionally to regulate the various Phase I/II genes shown. See Table 1 for a complete list of potential Phase I/II targets of HNF4α. See Figure 2 for additional interactions on the level of gene expression. See main text for references and additional detail.

Figure 2. Factors affecting HNF4α expression and function

A. The HNF4A gene is at the center of a complex transcriptional network of NR genes that are involved in xenobiotic and drug metabolism. All interactions are on the HNF4α P1 promoter except COUP-TF2 that acts on both the P1 and P2 promoter. See main text and [1] for references. B. Shown are broad categories of factors known to regulate the activity and level of HNF4α that could ultimately affect the expression of Phase I and Phase II genes and hence alter one’s ability to metabolize drugs. SNPs in the HNF4A gene as well as in the response elements bound by HNF4α protein could also account for some of the variability in drug metabolism among individuals. Shown is the position weight matrix for strong binders from [22]. ROS, reactive oxygen species. ?, effects not proven but are likely. See main text for references and additional detail.