Cholesterol detoxification by the nuclear pregnane X receptor

We have a love–hate relationship with cholesterol. On one hand, cholesterol is an essential component of cell membranes and serves as the precursor to steroid hormones and bile acids. On the other hand, cholesterol can clog blood vessels and give rise to cardiovascular disease. Moreover, oxidized metabolites of cholesterol, termed oxysterols, are cytotoxic in a variety of different cell types and contribute to atherosclerosis (1). Thus, it is crucial that excess cholesterol be removed from the body. In a recent issue of PNAS, Sonada et al. (2) described an unexpected role for the pregnane X receptor (PXR) in protecting against cholesterol toxicity. PXR is a member of the steroid/thyroid hormone receptor family of ligand-activated transcription factors that is expressed in liver, intestine, and kidney (3–5). Unlike the classical steroid hormone receptors, which are selectively activated by their cognate hormones at nanomolar or even picomolar concentrations, PXR is activated by micromolar concentrations of a structurally diverse collection of foreign chemicals, or xenobiotics, including the antibiotic rifampicin, the cancer drug taxol, and the herb Saint John's wort. This remarkable promiscuity is facilitated by the unusual ligand-binding pocket of PXR, which is both very large and smooth, allowing it to bind to many different chemicals (6). Once activated, PXR binds to DNA as a heterodimer with the retinoid X receptor and stimulates the transcription of genes encoding cytochrome P450 enzymes, conjugation enzymes, and transporters, which collectively promote xenobiotic metabolism. These findings have led to a “xenosensor” model (Fig. 1), in which PXR detects potentially harmful xenobiotics and induces genes that flush the offending chemicals from the …