HNF4α  role in drug metabolism and potential drug target?

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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.

Introduction

HNF4α (NR2A1), a highly conserved member of the nuclear receptor superfamily (NR) of ligand-dependent transcription factors (TFs), is known as a master regulator of liver-specific gene expression [1]. It was originally identified as an activity in rat liver that bound the APOC3 promoter and characterized as an orphan receptor as its ligand status was unknown [2]. It was subsequently identified as the gene mutated in Maturity Onset Diabetes of the Young 1 (MODY1), an inheritable form of non-insulin-dependent diabetes [3]. Therefore, HNF4α was initially known for its role in carbohydrate and lipid metabolism in the liver and its role in insulin signaling in the pancreas. Subsequently, cytochrome P450 (CYP) genes involved in xenobiotic and drug metabolism were identified as targets of HNF4α [4], although its role in those processes was eclipsed by that of ligand receptors. The recent identification of the endogenous ligand for HNF4α, as well as several genome-wide studies that have greatly expanded the repertoire of HNF4α targets, has renewed interest in the role of HNF4α in drug metabolism. In this review, we will discuss the key findings on this topic and how they relate to the notion of targeting HNF4α for drug discovery.

Section snippets

Background on drug metabolism and HNF4α

The detoxification of xenobiotics and metabolism of drugs occurs primarily in the liver and consists of two phases. Phase I is carried out by hundreds of cytochrome P450 enzymes (CYP450s) and a handful of flavin-containing monooxygenases (FMOs) that add or expose a polar functional group to lipophilic compounds. Phase II, which consists of conjugation reactions that help eliminate Phase I products from the body, is carried out by glutathione-S-transferases (GSTs), UDP-glucuronosyltransferase

Identification by classical means

Several CYP450 genes have been identified as HNF4α targets using classical means (e.g. promoter cloning, gel shift analysis, and reporter assays) and have been reviewed previously [8••] (Figure 1). Among the Phase I enzymes, CYP450 3A4 (CYP3A4) is arguably one of the most important as it is involved in the metabolism of nearly half of all drugs currently used. Early studies on CYP3A4 gene regulation focused on ligand-activated NRs, pregnane X receptor (PXR; NR1I2) and constitutive androstane

Transcriptional regulation network

Many NRs such as PXR, CAR, LXR, FXR, small heterodimer partner (SHP, NR0B2), Vitamin D receptor (VDR, NR1I1), chicken ovalbumin upstream promoter transcription factor (COUP-TF, NR2F1) and glucocorticoid receptor (GR, NR3C1) interact with HNF4α to regulate the expression of drug metabolism genes in a complex fashion (Figure 1). For example, HNF4α is involved in crosstalk with PXR and CAR on the promoters of the CYP3A4 [23], CYP2C8 [24], CYP2C9 [25], CYP7A1 [26, 27] and SULT2A1 [28] genes. While

Perspectives

It is now evident that HNF4α is a key player in the regulation of genes involved in drug metabolism. Indeed, since HNF4α is one of the most ancient of the NRs and since Cyp genes have equally ancient evolutionary origins [63], it is possible that HNF4α was the first NR to control the expression of this critical gene family in animals. The regulation of these genes, however, has evolved, just as the genes themselves. In addition to HNF4α, that regulation now involves many additional NRs, and

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize to all of our colleagues whose work we were not able to cite due to space limitations. WH-V is funded by a postdoctoral fellowship from Academia Sinica. The Sladek lab is funded by grants from the National Institutes of Health (DK053892 and MH087397).

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