Differential regulation of constitutive androstane receptor expression by hepatocyte nuclear factor4α isoforms

Abstract

Constitutive androstane receptor (CAR; NR1I3) controls the metabolism and elimination of endogenous and exogenous toxic compounds by up-regulating a battery of genes. In this work, we analyzed the expression of human CAR (hCAR) in normal liver during development and in hepatocellular carcinoma (HCC) and investigated the effect of hepatocyte nuclear factor 4␣ isoforms (HNF4␣1 and HNF4␣7) on the hCAR gene promoter. By performing functional analysis of hCAR 5-deletions including mutants, chromatin immunoprecipitation in human hepatocytes, electromobility shift and cotransfection assays, we identified a functional and species-conserved HNF4␣ response element (DR1: ccAGGCCTtTGCCCTga) at nucleotide ؊144. Both HNF4␣ isoforms bind to this element with similar affinity. However, HNF4␣1 strongly enhanced hCAR promoter activity whereas HNF4␣7 was a poor activator and acted as a repressor of HNF4␣1-mediated transactivation of the hCAR promoter. PGC1␣ stimulated both HNF4␣1-mediated and HNF4␣7-mediated hCAR transactivation to the same extent, whereas SRC1 exhibited a marked specificity for HNF4␣1. Transduction of human hepatocytes by HNF4␣7-expressing lentivirus confirmed this finding. In addition, we observed a positive correlation between CAR and HNF4␣1 mRNA levels in human liver samples during development, and an inverse correlation between CAR and HNF4␣7 mRNA levels in HCC. These observations suggest that HNF4␣1 positively regulates hCAR expression in normal developing and adult livers, whereas HNF4␣7 represses hCAR gene expression in HCC. (HEPATOLOGY 2007;45: 1146-1153.)

Xenobiotic Receptors CAR and PXR

“…In humans, hepatic CAR mRNA is also much lower in prenatals [98]. In both pediatric [98] and adult humans [119], hepatic CAR mRNA correlates highly with HNF4α mRNA, consistent with a key role of HNF4α1 in basal expression of CAR in mouse [58] and human liver [120]. The expression of human CAR and PXR is also controlled by glucocorticoids through the glucocorticoid receptor [121,122]; there is no evidence that mouse CAR or PXR expression is also controlled by the glucocorticoid receptor [123].…”

Correlation between Conjugated Bisphenol A Concentrations and Efflux Transporter Expression in Human Fetal Livers

“…In the human fetal liver, this trend corresponds with nominal expression of basal transcriptional regulators, including the nuclear hormone receptors constitutive androstane receptor and pregnane X receptor (Miki et al, 2005;Pascussi et al, 2007;de Sousa Abreu et al, 2009). Although expression of peroxisome proliferator-activated receptors is comparable between human fetal and adult livers, raw cross threshold (CT) values are high in both groups (Abbott et al, 2010 ABBREVIATIONS: BCRP, breast cancer resistance protein; BPA, bisphenol A; CT, cross threshold; LOQ, limit of quantification; MDR, multidrug resistance transporter; MRP, multidrug resistance-associated transporter; NQO1, NAD(P)H quinone oxidoreductase 1; NRF2, NF-E2-related factor 2; qPCR, quantitative polymerase chain reaction.…”

“…In the human fetal liver, this trend corresponds with nominal expression of basal transcriptional regulators, including the nuclear hormone receptors constitutive androstane receptor and pregnane X receptor (Miki et al, 2005;Pascussi et al, 2007;de Sousa Abreu et al, 2009). Although expression of peroxisome proliferator-activated receptors is comparable between human fetal and adult livers, raw cross threshold (CT) values are high in both groups (Abbott et al, 2010).…”

Identification of proteomic changes during human liver development by 2D-DIGE and mass spectrometry

“…It is a complex dynamic process that involves mitosis, morphogenesis, differentiation, and maturation at specific times from the embryonic stage through adulthood and is accompanied by a shift in genetic and proteomic profiles, particularly of signaling molecules and transcription factors [1]. We know from animal and human studies that some genes are critical for normal development of the fetal liver [2][3][4][5][6][7]. However, little is known about the genetic cascade that results in such a complex multicellular organization.…”