CIRCADIAN TRANSCRIPTION OF THE CHOLESTEROL 7-ALPHA HYDROXYLASE GENE MAY INVOLVE THE LIVER-ENRICHED BZIP PROTEIN DBP

The liver-enriched transcription factor DBP is expressed with a string ent circadian rhythm. We present evidence that DBP is a regulator of t he circadian expression of the rat gene encoding cholesterol 7alpha hy droxylase (C7alphaH), the rate-limiting enzyme in the conversion of ch olesterol to bile acids. As with DBP, C7alphaH mRNA reaches peak level s in the evening, and its cycling is independent of daily food and lig ht cues. As predicted for a DBP target gene, the primary level of C7al phaH circadian expression is at the transcriptional level. DBP can act ivate the C7alphaH promoter in cotransfection assays through a cognate DNA site centered around -225. In nuclear extracts prepared by a nove l method that, in contrast to conventional techniques, yields near-qua ntitative recovery of DBP and other non-histone proteins, the DNA site required for DBP activation is the predominant site of occupancy by n uclear factors on the C7alphaH promoter. At this site, the predominant binding activity is an evening-specific complex of which DBP is a com ponent. These data suggest that DBP may play an important role in chol esterol homeostasis through circadian transcriptional regulation of ch olesterol 7alpha hydroxylase.