Regulation of squalene synthetase in human hepatoma cell line Hep G2 by sterols, and not by mevalonate-derived non-sterols.
Incubations of Hep G2 cells for 18 h with human low-density lipoprotein (LDL) resulted in a decrease of squalene synthetase activity, whereas heavy high-density lipoprotein (hHDL) stimulated the activity. Simultaneous addition of LDL abolished the hHDL-induced stimulation, indicating that manipulating the regulatory sterol pool within the cells influenced the enzyme activity. Blocking the endogenous cholesterol synthesis either at the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase site with compactin or at the 2,3-oxidosqualene cyclase site with the inhibitor U18666A gave rise to an elevation of the squalene synthetase activity. Simultaneous addition of mevalonate abolished the compactin-induced increase. However, at total blockade of sterol synthesis by 30 microM U18666A, added compactin and/or mevalonate did not change the enzyme activity further. It was concluded that sterols regulate the squalene synthetase activity, whereas, in contrast with the regulation of the HMG-CoA reductase activity in Hep G2 cells, mevalonate-derived non-sterols did not influence this enzyme.
Cohen
L H
LH
Gaubius Institute TNO, Leiden, The Netherlands.
van Miert
E
E
Griffioen
M
M
D000736:Androstenes / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology*; D002784:Cholesterol / Q000096:biosynthesis; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019751:Intramolecular Transferases; D007535:Isomerases / Q000037:antagonists & inhibitors; D008075:Lipoproteins, HDL / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008113:Liver Neoplasms / Q000201:enzymology*; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology*; D010088:Oxidoreductases / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000736:Androstenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D013261:Sterols; C012258:mevastatin; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D002784:Cholesterol; D008148:Lovastatin; D010088:Oxidoreductases; D013186:Farnesyl-Diphosphate Farnesyltransferase; D007535:Isomerases; D019751:Intramolecular Transferases; C021924:lanosterol synthase; D008798:Mevalonic Acid