Hepatocyte nuclear factor 1 binds to and transactivates the human but not the rat CYP7A1 promoter

Abstract

Cholesterol 7alpha-hydroxylase (CYP7A1), a liver-specific enzyme, catalyzes the rate-limiting step in the degradation pathway of cholesterol to bile acids, and thus plays a key role in cholesterol homeostasis. To elucidate the mechanisms that control hepatic expression of the human CYP7A1 gene, we are studying the promoter region. Initially, we observed that up to 40% of the overall transcriptional activity of the promoter in HepG2 cells was associated with DNA sequences from -65 to -1 of the human gene. Within this region, a binding site for the liver-enriched transcription factor HNF-1 (-56 to -49) has been identified. Binding of HNF-1 to this site leads to transcriptional activation of the human promoter. The corresponding segment from the rat CYP7A1 gene does not bind HNF-1; instead, it is bound by the orphan receptors ARP-1 (COUP-TFII) and LXRalpha, that are implicated in dietary regulation.