Transcriptional Regulation of Cytochrome P450 Genes by the Nuclear Receptor Hepatocyte Nuclear Factor 4-Alpha

Abstract

Hepatocyte nuclear factor 4-alpha (HNF4alpha, NR2A1) is a nuclear receptor (NR) required for liver development and for controlling the expression of many hepatic-specific genes associated with important metabolic pathways. Many studies have also identified HNF4alpha as a direct transactivator of numerous xenobiotic-metabolizing cytochrome P450 (CYP) genes, suggesting that this factor is a global regulator which supports CYP transcription in the liver. Moreover, HNF4alpha expression displays a significant variability in human liver which may account for a proportion of the inter-individual variability in the expression of drug-metabolism genes and the clearance rate of a wide variety of prescribed drugs. In the last few years, a number of complex interactions and cross-talks between HNF4alpha and other transcription factors and coregulators have also surfaced, and the impact on CYP gene expression has been demonstrated. Thus, it is now clear that HNF4alpha modulates CYP expression in the liver by interacting with the xenosensor receptors (PXR and CAR), the glucocorticoid receptor (GR), the feeding-fasting cycle target PGC-1alpha, the sexual-dimorphism factor Stat5b, and other liver-enriched factors, such as C/EBPs. In addition to regulating drug elimination pathways, HNF4alpha also triggers pleiotropic effects on cholesterol and fatty acid metabolism, glucose homeostasis and inflammation. As a whole, current evidence indicates that HNF4alpha is a central regulator in the network of NRs that integrates drug-metabolism not only with the liver intermediate metabolism, but also with a number of patho-physiological conditions where the CYP expression is altered. The purpose of this review is to summarize and discuss these studies and their conclusions, with particular emphasis on the role of HNF4alpha in the regulation of drug-metabolizing CYP genes in the human liver.

Expression of Hepatic Drug-Metabolizing Cytochrome P450 Enzymes and Their Intercorrelations: A Meta-Analysis

“…0.5) (Mimura et al, 1993;Totah et al, 2008;Achour et al, 2014a), this correlation was weaker on analysis of all the collected data (Rs = 0.46, P , 0.0001, n = 124, five studies). Correlations of expression have also been reported at the mRNA level (Wortham et al, 2007), which further supports reports of common genetic regulation of the expression of cytochrome P450 enzymes (Jover et al, 2009). …”

“…All the correlations observed were positive, and although this would be expected [correlation arising from common regulatory receptors and pathways (Wortham et al, 2007;Jover et al, 2009)], there appears to be a background positive correlation between all the cytochrome P450 enzymes under study. The background correlation is a necessary artifact of measuring abundance levels in units of pmol mg…”

“…Hence, these data can be used for simulation experiments involving virtual populations for the pharmacologic and toxicologic assessment of drugs (Rostami-Hodjegan and Tucker, 2007). Correlations of expression between enzymes have been reported in the literature (Jover et al, 2009), and although in the current framework of Monte-Carlo simulations for creating virtual populations (Rostami-Hodjegan and Tucker, 2007) these correlations are not considered, such correlations, if established, can assist in producing more reliable scenarios.…”

Transcription Factors Potentially Involved in Regulation of Cytochrome P450 Gene Expression

“…Because miR-24 and miR-34a are regulated by oxidative stress, it is considered that they play a negative role in the pathogenesis of liver diseases (Takagi et al, 2010). The fact that the natural HNF-4 ligand is linolenic acid, suggests the possibility of regulating its activity by the diet and pharmacological modulation (Gonzalez, 2008;Hwang-Verslues & Sladek, 2010;Jover et al, 2009). …”

“…Among them are signaling pathways dependent on NF-κB, MAP kinases, and -catenin (Braeuning, 2009;Murray et al, 2010;Zordoky & El-Kadi, 2009). Glucocorticoid receptor and GATA4, Nrf2 and C/EBP transcription factors also play important role in the transcriptional regulation of cytochromes P450 (Dvorak & Pavek, 2010;Jover et al, 2009;Mwinyi et al, 2010a;Yokota et al, 2011). It can not be excluded that there are significant functional dependencies allowing for the hormonal control of the mentioned signaling pathways.…”