Pharmacological evidence for a role of liver X receptors in atheroprotection

Nuclear receptors, such as LXR (liver X receptor), bind to DNA cis elements, known as hormone response elements, and activate transcription of their speci¢c target genes [1]. LXR was originally termed orphan nuclear receptor because its natural ligand was unknown at the time that it was initially cloned. With the recent identi¢cation of physiological ligands that activate LXR, this orphan is now ‘adopted’ [2]. LXR was originally isolated from a human cDNA library [3], and later two isoforms were identi¢ed, LXRK and LXRL. Both isoforms bind RXR (9-cis retinoic acid receptor) to form a heterodimer, and the heterodimers bind to the hormone response element DR4. Oxidized forms of cholesterol (oxysterols), which are intermediary substrates in the rate-limiting steps of steroid hormone biosynthesis, of bile acid synthesis, and in the conversion of lanosterol to cholesterol, have been identi¢ed as the potential physiological ligands for LXRs [4]. These ¢ndings strongly suggest that LXRs play a role in the cholesterol homeostasis of the body. Indeed, several important genes encoding proteins involved in body cholesterol transport have been shown to be regulated by LXRs. In addition, LXRs have also been shown to a¡ect major genes encoding proteins that control triglyceride metabolism. Thus, LXRs appear to provide peripheral tissues with fatty acids while bringing cholesterol back to the liver (Fig. 1).