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.