Transcriptional regulation of cholesterol metabolism

Sterols and cholesterol in particular are lipids that have been studied exh austively in view of their vital role in diverse cellular functions. Recent ly, it has been recognized that cholesterol is not only an essential compon ent for the formation of membranes and the synthesis of steroid hormones an d bile acids, but also is a key molecule in caveolae formation and embryoni c development. Intracellular cholesterol can be derived exogenously from th e plasma via receptor-mediated uptake or endogenously via de novo biosynthe sis, However, as a consequence of the toxic effects of excess cholesterol i n the cell and the well established contribution of hypercholesteremia to a therosclerotic diseases, it is of most importance to control cholesterol ho meostasis as efficiently as possible. Until now, the regulation of the cont ent of intracellular cholesterol was thought to be predominantly achieved b y a feedback mechanism controlling a variety of genes involved in cholester ol biosynthesis and cholesterol uptake. The key factor in this process is a basic helix loop helix - leucine zipper protein, designated ADD-1/SREBP, a transcription factor activated by a cholesterol - dependent proteolytic sy stem. Only recently, a new group of nuclear hormone receptors has been disc overed that control the activation of diverse pathways involved in the util isation of cholesterol. These receptors, including LXR, SF-1, FXR, and the recently identified receptors PXR and SXR, are activated by cholesterol int ermediates or derivatives, The identification of sterol-activated nuclear r eceptors opens up a whole new area in the lipid and endocrinology research field. A better comprehension of the mechanism of action and the physiologi cal role of these receptors will undoubtedly contribute to find new therape utic ways in the treatment of metabolic disorders linked to an abberated ch olesterol metabolism.