Hepatocyte nuclear factor 4 alpha (HNF4a) is a liver-enriched master regulator of liver function. HNF4a is important in regulating hepatic expression of certain
cytochrome P450s. The purpose of this study was to use mice lacking HNF4a expression in liver (HNF4a-HNull) to elucidate the role of HNF4a in regulating hepatic expression of phase II
enzymes and transporters in mice. Compared with male wild-type mice, HNF4a-HNull male mouse livers had (1) markedly lower messenger RNAs (mRNAs) encoding the uptake transporters
sodium taurocholate cotransporting polypeptide, organic
anion transporting
polypeptide (Oatp) 1a1, Oatp2b1,
organic anion transporter 2,
sodium phosphate cotransporter type 1,
sulfate anion transporter 1,
sodium-dependent vitamin C transporter 1, the phase II
enzymes Uridine 5'-diphospho (
UDP)-glucuronosyltransferase (Ugt) 2a3, Ugt2b1, Ugt3a1, Ugt3a2,
sulfotransferase (Sult) 1a1, Sult1b1, Sult5a1, the efflux transporters
multidrug resistance-associated protein (Mrp) 6, and multidrug and toxin extrusion 1; (2) moderately lower mRNAs encoding Oatp1b2, organic
cation transporter (Oct) 1, Ugt1a5, Ugt1a9,
glutathione S-transferase (Gst) m4, Gstm6, and
breast cancer resistance
protein; but (3) higher mRNAs encoding Oatp1a4, Octn2, Ugt1a1, Sult1e1, Sult2a2, Gsta4, Gstm1-m3, multidrug resistance
protein (Mdr) 1a, Mrp3, and Mrp4. Hepatic signaling of
nuclear factor E2-related factor 2 and
pregnane X receptor appear to be activated in HNF4a-HNull mice. In conclusion, HNF4a deficiency markedly alters hepatic
mRNA expression of a large number of phase II
enzymes and transporters, probably because of the loss of HNF4a, which is a
transactivator and a determinant of gender-specific expression and/or adaptive activation of signaling pathways important in hepatic regulation of these phase II
enzymes and transporters.