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In addition to their digestive actions, bile acids modulate gene expression by altering the activity of peroxisome proliferator-activated receptor-α(PPARα). The modulatory effects of bile acids have been shown to affect the expression of genes responsible for lipid metabolism as well as membrane transporters. Bile acids are secreted in response to food intake and accumulate in intestinal epithelial cells. In the present study, we identified soluble carrier protein family 22 member 4 (Slc22a4), encoding organic cation transporter novel type-1 (Octn1), as a PPARα-regulated gene and its intestinal expression exhibited circadian oscillations in a bile acid–dependent manner. Nocturnally active mice mainly consumed their food around the early dark phase, during which bile acids accumulated in intestinal epithelial cells. PPARαactivated the intestinal expression of Slc22a4mRNA during the light period, and protein levels of Octn1 peaked before the start of the dark phase. The bile acids that accumulated in intestinal epithelial cells suppressed the PPARα-mediated transactivation of Slc22a4in the dark phase. The time-dependent suppression of PPARα-mediated transactivation by bile acids regulated oscillations in the intestinal expression of Octn1/Slc22a4during the daily feeding cycle. The results of a pharmacokinetic analysis also revealed that oscillations in the expression of Octn1 caused dosing time-dependent differences in the intestinal absorption of gabapentin (2-[1-(aminomethyl)cyclohexyl]acetic acid). These results suggest a molecular clock–independent mechanism by which bile acid–regulated PPARαactivity governs the circadian expression of intestinal organic cation transporters. This mechanism could also account for interindividual variations in the pharmacokinetics of drugs that are substrates of Octn1.

Differentiated embryo chondrocyte-2 (DEC2), also known as bHLHE41 or Sharp1, is a pleiotropic transcription repressor that controls the expression of genes involved in cellular differentiation, hypoxia responses, apoptosis, and circadian rhythm regulation. Although a previous study demonstrated that DEC2 participates in the circadian control of hepatic metabolism by regulating the expression of cytochrome P450, the molecular mechanism is not fully understood. We reported previously that brief exposure of HepG2 cells to 50% serum resulted in 24-h oscillation in the expression of CYP3A4 as well as circadian clock genes. In this study, we found that the expression of CYP2D6, a major drug-metabolizing enzyme in humans, also exhibited a significant oscillation in serum-shocked HepG2 cells. DEC2 interacted with CCAAT/enhancer-binding protein (C/EBPα), accompanied by formation of a complex with histone deacetylase-1, which suppressed the transcriptional activity of C/EBPα to induce the expression of CYP2D6. The oscillation in the protein levels of DEC2 in serum-shocked HepG2 cells was nearly antiphase to that in the mRNA levels of CYP2D6. Transfection of cells with small interfering RNA against DEC2 decreased the amplitude of CYP2D6 mRNA oscillation in serum-shocked cells. These results suggest that DEC2 periodically represses the promoter activity of CYP2D6, resulting in its circadian expression in serum-shocked cells. DEC2 seems to constitute a molecular link through which output components from the circadian clock are associated with the time-dependent expression of hepatic drug-metabolizing enzyme.