Régulation transcriptionnelle du métabolisme du cholestérol.

Abstract

Si les sterols et le cholesterol en particulier sont indispensables a la fonction de la cellule et au developpement embryonnaire, un exces de cholesterol peut etre toxique au niveau cellulaire et conduire a des affections atherosclerotiques au niveau des vaisseaux. Il est donc particuliere ment utile de pouvoir controler de facon efficace son homeostasie. La concentration intracellulaire de cholesterol est reglee par plusieurs mecanismes: (1) un retrocontrole negatif de l' expression de genes necessaires a sa biosynthese et a son captage qui implique le facteur de transcription ADD-1/SREBP ; (2) la stimulation de l' expression de genes permettant son utilisation qui met en jeu un nouveau groupe de recepteurs hormonaux nucleaires (LXR, SF-1...). L' identification de ces facteurs de transcription actives par les sterols et la comprehension de leur fonction ouvrent de nouvelles voies de recherche du metabolisme lipidique, ainsi que des perspectives cliniques et therapeutiques dans les domaines de l' endocrinologie.

Sterols and cholesterol in particular are lipids that have been studied exhaustively in view of their vital role in diverse cellular functions. Recently, it has been recognized that cholesterol is not only an essential component for the formation of membranes and the synthesis of steroid hormones and bile acids, but also is a key molecule in caveolae formation and embryonic development. Intracellular cholesterol can be derived exogenously from the plasma via receptor-mediated uptake or endogenously via de novo biosynthesis. However, as a consequence of the toxic effects of excess cholesterol in the cell and the well established contribution of hypercholesteremia to atherosclerotic diseases, it is of most importance to control cholesterol homeostasis as efficiently as possible. Until now, the regulation of the content of intracellular cholesterol was thought to be predominantly achieved by a feedback mechanism controlling a variety of genes involved in cholesterol 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 system. Only recently, a new group of nuclear hormone receptors has been discovered that control the activation of diverse pathways involved in the utilisation of cholesterol. These receptors, including LXR, SF-1, FXR, and the recently identified receptors PXR and SXR, are activated by cholesterol intermediates or derivatives. The identification of sterol-activated nuclear receptors opens up a whole new area in the lipid and endocrinology research field. A better comprehension of the mechanism of action and the physiological role of these receptors will undoubtedly contribute to find new therapeutic ways in the treatment of metabolic disorders linked to an abberated cholesterol metabolism. [References: 41]