HNF4α — role in drug metabolism and potential 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).
References (66)
- et al.
The xenobiotic-sensing nuclear receptors pregnane X receptor, constitutive androstane receptor, and orphan nuclear receptor hepatocyte nuclear factor 4alpha in the regulation of human steroid-/bile acid-sulfotransferase
Mol Endocrinol
(2007) - et al.
Hepatocyte nuclear factor 1 alpha and 4 alpha are factors involved in interindividual variability in the expression of UGT1A6 and UGT1A9 but not UGT1A1, UGT1A3 and UGT1A4 mRNA in human livers
Drug Metab Pharmacokinet
(2007) - et al.
Hepatocyte nuclear factor1 transcription factors are essential for the UDP-glucuronosyltransferase 1A9 promoter response to hepatocyte nuclear factor 4alpha
Pharmacogenet Genomics
(2007) Analysis of sequence specificities of DNA-binding proteins with protein binding microarrays
Methods Enzymol
(2006)- et al.
Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4alpha
Mol Pharmacol
(2005) - et al.
The small heterodimer partner interacts with the pregnane X receptor and represses its transcriptional activity
Mol Endocrinol
(2003) Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms
J Hepatol
(2004)- et al.
Identification of an endogenous ligand bound to a native orphan nuclear receptor
PLoS One
(2009) - et al.
Nuclear receptor coactivator 6 mediates the synergistic activation of human cytochrome P-450 2C9 by the constitutive androstane receptor and hepatic nuclear factor-4alpha
Mol Pharmacol
(2008) - et al.
The MODY1 gene for hepatocyte nuclear factor 4alpha and a feedback loop control COUP-TFII expression in pancreatic beta cells
Mol Cell Biol
(2008)
MicroRNAs regulate human hepatocyte nuclear factor 4alpha, modulating the expression of metabolic enzymes and cell cycle
J Biol Chem
4Beta-hydroxycholesterol is a new endogenous CYP3A marker: relationship to CYP3A5 genotype, quinine 3-hydroxylation and sex in Koreans, Swedes and Tanzanians
Pharmacogenet Genomics
Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1
Nature
Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily
Genes Dev
Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young
Hum Mutat
Hepatocyte Nuclear Factor 4α
Principles of Toxicology
Control of pancreas and liver gene expression by HNF transcription factors
Science
Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding
Science
Transcriptional regulation of cytochrome p450 genes by the nuclear receptor hepatocyte nuclear factor 4-alpha
Curr Drug Metab
Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor
Mol Pharmacol
The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module
Mol Pharmacol
The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4
Nat Med
Involvement of hepatocyte nuclear factor 4alpha in the different expression level between CYP2C9 and CYP2C19 in the human liver
Drug Metab Dispos
Cytochrome P450 regulation by hepatocyte nuclear factor 4 in human hepatocytes: a study using adenovirus-mediated antisense targeting
Hepatology
Role of human hepatocyte nuclear factor 4alpha in the expression of drug-metabolizing enzymes and transporters in human hepatocytes assessed by use of small interfering RNA
Drug Metab Pharmacokinet
Regulation of flavin-containing monooxygenase 1 expression by ying yang 1 and hepatic nuclear factors 1 and 4
Mol Pharmacol
Differential regulation of alternate UDP-glucuronosyltransferase 1A6 gene promoters by hepatic nuclear factor-1
Toxicol Appl Pharmacol
Hepatic expression of the UGT1A9 gene is governed by hepatocyte nuclear factor 4alpha
Mol Pharmacol
Integrated approach for the identification of human hepatocyte nuclear factor 4alpha target genes using protein binding microarrays
Hepatology
Rifampicin induction of CYP3A4 requires pregnane X receptor cross talk with hepatocyte nuclear factor 4alpha and coactivators, and suppression of small heterodimer partner gene expression
Drug Metab Dispos
The nuclear receptors constitutive androstane receptor and pregnane X receptor cross-talk with hepatic nuclear factor 4alpha to synergistically activate the human CYP2C9 promoter
J Pharmacol Exp Ther
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