The effects of lifibrol (K12.148) on the cholesterol metabolism of cultured cells: evidence for sterol independent stimulation of the LDL receptor pathway.
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.
Scharnagl
H
H
Department of Medicine, Divison of Clinical Chemistry, Albert Ludwigs-University, Hugstetter Strasse 55, 79106, Freiburg, Germany. hubsch@medl.ukl.uni-freiburg.de
Schliack
M
M
Löser
R
R
Nauck
M
M
Gierens
H
H
Jeck
N
N
Wieland
H
H
Gross
W
W
März
W
W
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000440:Butanols / Q000494:pharmacology*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D062385:Hydroxybenzoates / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D011355:Prodrugs / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D013261:Sterols / Q000037:antagonists & inhibitors / Q000378:metabolism
D000924:Anticholesteremic Agents; D000440:Butanols; D062385:Hydroxybenzoates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011355:Prodrugs; D011973:Receptors, LDL; D013261:Sterols; C059343:lifibrol; D002784:Cholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases