Sterols and gene expression: control of affluence

Intracellular and extracellular cholesterol levels are tightly maintained w ithin a narrow concentration range by an intricate transcriptional control mechanism. Excess cholesterol can be converted into oxysterols, signaling m olecules, which modulate the activity; of a number of transcription factors , as to limit accumulation of excess of cholesterol. Two key regulatory pat hways are affected by oxysterols. The first pathway involves the uptake and de novo synthesis of cholesterol and is controlled by the family of sterol response element binding proteins, whose activity is regulated by a sterol -dependent feedback mechanism. The second pathway, which only recently has become a topic of interest, involves the activation by a feedforward mechan ism of cholesterol utilization for either bile acid or steroid hormone synt hesis by oxysterol-activated nuclear receptors, such as liver X receptor an d steroidogenic factor-1. Furthermore, biosynthesis and enterohepatic reabs orption of bile acids are regulated by the farnesol X receptor, a receptor activated by bile acids. Both the feedback inhibition of cholesterol uptake and production and the stimulation of cholesterol utilization will ultimat ely result in a lowering of the intracellular cholesterol concentration and allow for a fine-tuned regulation of the cholesterol concentration. (C) 20 00 Elsevier Science B.V. All rights reserved.