Lifibrol (4-(4'-tert. butylphenyl)-1-(4'-carboxyphenoxy)-2-butanol) is a new hypocholesterolemic compound; it effectively lowers
low density lipoprotein (
LDL) cholesterol. We studied the effects of
lifibrol on the
cholesterol metabolism of cultured cells. In the
hepatoma cell line HepG2,
Lifibrol decreased the formation of
sterols from [14C]-
acetic acid by approximately 25%. Similar to
lovastatin,
lifibrol had no effect on the synthesis of
sterols from [14C]-
mevalonic acid.
Lifibrol did not inhibit
3-hydroxy-3-methylglutaryl-coenzyme A (
HMG-CoA) reductase. Instead,
cholesterol synthesis inhibition by
lifibrol was entirely accounted for by competitive inhibition of
HMG-CoA synthase.
Lifibrol enhanced the cellular binding, uptake, and degradation of
LDL in cultured cells in a dose dependent fashion. The stimulation of
LDL receptors was significantly stronger than expected from the effect of
lifibrol on
sterol synthesis. In parallel,
lifibrol increased the amount of immunologically detectable receptor
protein. Stimulation of
LDL receptor mediated endocytosis was observed both in the presence and in the absence of
cholesterol-containing
lipoproteins. In the absence of an extracellular source of
cholesterol, both
lifibrol and
lovastatin induced microsomal
HMG-CoA reductase. Co-incubation with
LDL was sufficient to suppress the
lifibrol mediated increase in
reductase activity, indicating that
lifibrol does not affect the production of the non-
sterol derivative(s) which are thought to regulate
HMG-CoA reductase activity at the post-transcriptional level. Considered together, the data suggest that the hypolipidemic action of
lifibrol may, at least in part, be mediated by
sterol-independent stimulation of the
LDL receptor pathway. A potential advantage of
lifibrol is that therapeutic concentrations do not interfere with the production of
mevalonate which is required not only to synthesize
sterols but also as a precursor of electron transport moieties,
glycoproteins and farnesylated
proteins.