Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor - PubMed (original) (raw)

. 2000 Sep 8;275(36):28240-5.

doi: 10.1074/jbc.M003337200.

Affiliations

Free article

Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor

P Costet et al. J Biol Chem. 2000.

Free article

Abstract

Tangier disease, a condition characterized by low levels of high density lipoprotein and cholesterol accumulation in macrophages, is caused by mutations in the ATP-binding cassette transporter ABC1. In cultured macrophages, ABC1 mRNA was induced in an additive fashion by 22(R)-hydroxycholesterol and 9-cis-retinoic acid (9CRA), suggesting induction by nuclear hormone receptors of the liver X receptor (LXR) and retinoid X receptor (RXR) family. We cloned the 5'-end of the human ABC1 transcript from cholesterol-loaded THP1 macrophages. When transfected into RAW macrophages, the upstream promoter was induced 7-fold by 22(R)-hydroxycholesterol, 8-fold by 9CRA, and 37-fold by 9CRA and 22(R)-hydroxycholesterol. Furthermore, promoter activity was increased in a sterol-responsive fashion when cotransfected with LXRalpha/RXR or LXRbeta/RXR. Further experiments identified a direct repeat spaced by four nucleotides (from -70 to -55 base pairs) as a binding site for LXRalpha/RXR or LXRbeta/RXR. Mutations in this element abolished the sterol-mediated activation of the promoter. The results show sterol-dependent transactivation of the ABC1 promoter by LXR/RXR and suggest that small molecule agonists of LXR could be useful drugs to reverse foam cell formation and atherogenesis.

PubMed Disclaimer

Similar articles

Cited by

Publication types

MeSH terms

Substances

LinkOut - more resources