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

Tangier disease, a condition characterized by low levels of high density li poprotein and cholesterol accumulation in macrophages, is caused by mutatio ns in the ATP-binding cassette transporter ABC1. In cultured macrophages, A BC1 mRNA was induced in an additive fashion by 22(R)-hydroxycholesterol and 9-cis-retinoic acid (9CRA), suggesting induction by nuclear hormone recept ors 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)-hydrosyeholesterol, 8-fold by 9CRA, and 37-fold by 9CRA and 22(R)-hydroxycholesterol. Furthermore, promoter activity was i ncreased in a sterol-responsive fashion when cotransfected with LXR alpha/R XR or LXR beta/RXR, Further experiments identified a direct repeat spaced b y four nucleotides (from -70 to -55 base pairs) as a binding site for LXR a lpha/RXR or LXR beta/RXR, Mutations in this element abolished the sterol-me diated activation of the promoter. The results show sterol-dependent transa ctivation of the ABC1 promoter by LXR/RXR and suggest that small molecule a gonists of LXR could be useful drugs to reverse foam cell formation and ath erogenesis.