From gallstones to genes: two hundred years of sterol research. A tribute to George J. Schroepfer Jr.

The origins of cholesterol research can be traced to prerevolutionary France. The discovery of cholesterol as a single substance, present in human gallstones, owes much to the scientists of l'Académie Française, including Lavoisier, who contributed so much to the emergence of chemistry as a modern scientific discipline. Since that time, cholesterol probably has been the most intensively scrutinized natural product of all time, and it has been the subject of Nobel Prizes for several who have studied its structure, biosynthesis, and regulation. The pace of research into cholesterol shows no sign of diminishing, and recent discoveries have led to the recognition that the regulation of cholesterol metabolism is intimately linked with that of other metabolic pathways. Details of these interactions are only just emerging, but it is becoming apparent that under some circumstances it is difficult to reconcile, in a conventional manner, changes in regulatory gene expression with corresponding changes in pathway carbon flux. The present review includes some of our studies on the roles of the transcription factors sterol regulatory element-binding protein, liver X-receptor alpha, and peroxisome proliferator activated receptor a in the coordination of cholesterol and fatty acid synthesis and describes how some of the results obtained can best be interpreted from a Metabolic Control Analysis perspective of the regulation of pathway carbon fluxes.