CYP3A4 is a major drug-metabolizing enzyme in humans, whose expression levels show large interindividual variations and are associated with several factors such as genetic polymorphism, physiological and disease status, diet and xenobiotic exposure. Nuclear receptor pregnane X receptor (PXR) is a key transcription factor for the xenobiotic-mediated transcription of CYP3A4. In this study, we have investigated a possible involvement of liver X receptor a (LXRa), a critical regulator of cholesterol homeostasis, in the hepatic CYP3A4 expression since several recent reports suggest the involvement of CYP3A enzymes in the cholesterol metabolism in humans and mice. Reporter assays using wild-type and mutated CYP3A4 luciferase reporter plasmids and electrophoretic mobility shift assays revealed that LXRa up-regulated CYP3A4 through the known DNA elements critical for the PXR-dependent CYP3A4 transcription, suggesting LXRa as a positive regulator for the CYP3A4 expression and a crosstalk between PXR and LXRa in the expression. In fact, reporter assays showed that LXRa activation attenuated the PXR-dependent CYP3A4 transcription. Moreover, a PXR agonist treatment-dependent increase in CYP3A4 mRNA levels was suppressed by co-treatment with an LXRa agonist in human primary hepatocytes and HepaRG cells. The suppression was not observed when LXRa expression was knocked-down in HepaRG cells. In conclusion, the present results suggest that sterol-sensitive LXRa positively regulates the basal expression of CYP3A4 but suppresses the xenobiotic/PXR-dependent CYP3A4 expression in human hepatocytes. Therefore, nutritional, physiological and disease conditions affecting LXRa might be one of the determinants for the basal and xenobiotic-responsive expression of CYP3A4 in human livers.
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