Regulation of cholesterol 7 alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXR alpha)

The cholesterol 7 alpha -hydroxylase gene (CYP7A1) plays an important role in regulation of bile acid biosynthesis and cholesterol homeostasis. Oxyste rol receptor, LXR, stimulates, whereas the bile acid receptor, FXR, inhibit s CYP7A1 transcription. The goal of this study was to investigate the role of LXR alpha on the regulation of rat, human and hamster CYP7A1 transcripti on in its native promoter and cellular context. Cotransfection with LXR alp ha and RXR alpha expression plasmids strongly stimulated rat CYP7A1/lucifer ase reporter activity in HepG2 cells and oxysterol was not required. Howeve r, LXR alpha had much less effect on hamster and no significant effect on h uman CYP7A1 promoter activity in HepG2 cells. In Chinese hamster ovary cell s, cotransfection with LXR alpha stimulated reporter activity by less than 2-fold and addition of 22(R)-hydroxycholesterol caused a small but signific ant stimulation of rat, human and hamster CYP7A1 promoter activity. At leas t two direct repeats of AGGTCA-like sequences with 4-base spacing (DR4) and five-base spacing (DR5), in previously identified bile acid response eleme nts of the rat CYP7A1 were able to bind LXR alpha /RXR alpha and confer LXR alpha stimulation. However, LXR alpha did not bind to the corresponding se quences of the human gene and bound weakly to hamster and mouse DR4 sequenc es. Therefore, rats and mice have the unusual capacity to convert cholester ol to bile acids by LXR alpha -mediated stimulation of CYP7A1 transcription , whereas other species do not respond to cholesterol and develop hyperchol esterolemia on a diet high in cholesterol. (C) 2001 Elsevier Science B.V. A ll rights reserved.