Do oxysterols control cholesterol homeostasis?

Oxysterols are oxygenated derivatives of cholesterol with a very short half-life relative to cholesterol.As a consequence they are present in very low concentrations in all mammalian systems, almost invariably accompanied by 10 3 -to 10 6 -fold excess of cholesterol.Oxysterols are important intermediates in a number of hepatic and extrahepatic catabolic pathways, most of which generate water-soluble bile acids as final products.Based on largely indirect evidence, and in spite of their low levels in vivo, oxysterols are generally believed to be important physiological mediators of cholesterol-induced effects.Perhaps the best support for this model is the existence of nuclear receptors that bind these compounds with high affinity and the fact that oxysterols potently regulate the expression of sterol-sensitive genes in vitro.Here I consider the role of oxysterols as intermediates in different catabolic pathways, and I weigh the evidence for and against the "oxysterol hypothesis" of cholesterol homeostasis.