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

Title

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

Creator

Chiang J Y; Kimmel R; Stroup D

Publisher

Gene

Date

2001
2001-01

Description

The cholesterol 7alpha-hydroxylase gene (CYP7A1) plays an important role in regulation of bile acid biosynthesis and cholesterol homeostasis. Oxysterol receptor, LXR, stimulates, whereas the bile acid receptor, FXR, inhibits CYP7A1 transcription. The goal of this study was to investigate the role of LXRalpha on the regulation of rat, human and hamster CYP7A1 transcription in its native promoter and cellular context. Cotransfection with LXRalpha and RXRalpha expression plasmids strongly stimulated rat CYP7A1/luciferase reporter activity in HepG2 cells and oxysterol was not required. However, LXRalpha had much less effect on hamster and no significant effect on human CYP7A1 promoter activity in HepG2 cells. In Chinese hamster ovary cells, cotransfection with LXRalpha stimulated reporter activity by less than 2-fold and addition of 22(R)-hydroxycholesterol caused a small but significant stimulation of rat, human and hamster CYP7A1 promoter activity. At least two direct repeats of AGGTCA-like sequences with 4-base spacing (DR4) and five-base spacing (DR5), in previously identified bile acid response elements of the rat CYP7A1 were able to bind LXRalpha/RXRalpha and confer LXRalpha stimulation. However, LXRalpha did not bind to the corresponding sequences of the human gene and bound weakly to hamster and mouse DR4 sequences. Therefore, rats and mice have the unusual capacity to convert cholesterol to bile acids by LXRalpha-mediated stimulation of CYP7A1 transcription, whereas other species do not respond to cholesterol and develop hypercholesterolemia on a diet high in cholesterol.

Subject

Humans; Animals; Binding Sites; Rats; Species Specificity; Transfection; Gene Expression Regulation/drug effects; Organ Specificity; Transcription Factors/genetics/metabolism; Cricetinae; Response Elements; Luciferases/genetics/metabolism; Retinoid X Receptors; Cholesterol 7-alpha-Hydroxylase/drug effects/*genetics/metabolism; Hydroxycholesterols; Liver/physiology; Lovastatin/pharmacology; Mevalonic Acid/metabolism/pharmacology; Nicotinic Acids/pharmacology; Polyisoprenyl Phosphates/pharmacology; Tetrahydronaphthalenes/pharmacology; Cells; Cultured; Receptors; Transcription; Genetic; Retinoic Acid/genetics/metabolism; Steroid/genetics/*metabolism

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

257–265

Issue

1

Volume

262

Citation

Chiang J Y; Kimmel R; Stroup D, “Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha).,” NEOMED Bibliography Database, accessed June 22, 2021, https://neomed.omeka.net/items/show/5349.

Social Bookmarking