Circadian transcription of the cholesterol 7 alpha hydroxylase gene may involve the liver-enriched bZIP protein DBP.

Abstract

The liver-enriched transcription factor DBP is expressed with a stringent circadian rhythm. We present evidence that DBP is a regulator of the circadian expression of the rat gene encoding cholesterol 7 alpha hydroxylase (C7 alpha H), the rate-limiting enzyme in the conversion of cholesterol to bile acids. As with DBP, C7 alpha H mRNA reaches peak levels in the evening, and its cycling is independent of daily food and light cues. As predicted for a DBP target gene, the primary level of C7 alpha H circadian expression is at the transcriptional level. DBP can activate the C7 alpha H promoter in cotransfection assays through a cognate DNA site centered around -225. In nuclear extracts prepared by a novel method that, in contrast to conventional techniques, yields near-quantitative recovery of DBP and other non-histone proteins, the DNA site required for DBP activation is the predominant site of occupancy by nuclear factors on the C7 alpha H promoter. At this site, the predominant binding activity is an evening-specific complex of which DBP is a component. These data suggest that DBP may play an important role in cholesterol homeostasis through circadian transcriptional regulation of cholesterol 7 alpha hydroxylase.