CHOLESTEROL HOMEOSTASIS - MODULATION BY AMPHIPHILES

Diverse amphiphiles act on cellular cholesterol metabolism as if signa ling regulatory sites. One class (oxysterols) mimics the homeostatic e ffects of excess cell cholesterol, inhibiting cholesterol biosynthesis and stimulating plasma membrane cholesterol esterification. A second class of amphiphiles has effects precisely opposite to the oxysterols, i.e. they immediately inhibit plasma membrane cholesterol esterificat ion and progressively induce 3-hydroxy-3-methylglutaryl-coenzyme A red uctase activity and cholesterol biosynthesis. This second class of age nts includes steroids, hydrophobic amines, phenothiazines, ionophores, colchicine, cytochalasins, and lysophosphatides, most of which intera ct with P-glycoproteins. These data support a general hypothesis descr ibing cellular cholesterol homeostasis. (a) Proteins regulating sterol metabolism are embedded in intracellular membranes where their activi ties are governed by the local level of cholesterol. (b) Excess plasma membrane and lysosomal cholesterol circulates through those intracell ular membranes and sets the homeostatic activities therein. (c) The tw o classes of agents mentioned above affect cholesterol homeostasis by increasing or decreasing, respectively, the ambient level of cholester ol at the sites of regulation.