dc.contributor.author | Berkhout, Theo | |
dc.contributor.author | Simon, Helen M. | |
dc.contributor.author | Patel, Dilip D. | |
dc.contributor.author | Bentzen, Craig | |
dc.contributor.author | Niesor, Eric | |
dc.contributor.author | Jackson, Brian | |
dc.contributor.author | Suckling, Keith E. | |
dc.date.accessioned | 2014-06-11T10:00:32Z | |
dc.date.available | 2014-06-11T10:00:32Z | |
dc.date.issued | 1996-06-25 | |
dc.identifier.citation | Berkhout , T , Simon , H M , Patel , D D , Bentzen , C , Niesor , E , Jackson , B & Suckling , K E 1996 , ' The novel cholesterol-lowering drug SR-12813 inhibits cholesterol synthesis via an increased degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase ' , Journal of Biological Chemistry , vol. 271 , no. 24 , pp. 14376-14382 . https://doi.org/10.1074/jbc.271.24.14376 | |
dc.identifier.issn | 0021-9258 | |
dc.identifier.uri | http://hdl.handle.net/2299/13692 | |
dc.description.abstract | SR-12813 (tetra-ethyl 2-(3,5-di-tert-butyl-4-hydroxy-phenyl)ethenyl-1,1- bisphosphonate) lowers plasma cholesterol in five species. In this paper we investigate the underlying mechanism using Hep G2 cells. SB-12813 inhibited incorporation of tritiated water into cholesterol with an IC50 of 1.2 μM but had no effect on fatty acid synthesis. Furthermore, SR-12813 reduced cellular 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity with an IC50 of 0.85 μM. The inhibition of HMG-CoA reductase activity was rapid with a T( 1/2 ) of 10 min. After a 16-h incubation with SR-12813, mRNA levels of HMG-CoA reductase and low density lipoprotein (LDL) receptor were increased. The increased expression of LDL receptor translated into a higher LDL uptake, which can explain the primary hypocholesterolemic effect of SR- 12813 in vivo. Western blot analysis indicated that the amount of HMG-CoA reductase protein rapidly decreased in the presence of SR-12813. Pulse-chase experiments with [35S]methionine showed that the T( 1/2 ) of HMG-CoA reductase degradation decreased in the presence of SR-12813 from 90 to 20 min. Pre- incubation with 50 μM of lovastatin did not prevent the effects of SR-12813 on HMG-CoA reductase degradation, indicating that the compound does not need mevalonate-derived regulators for its action. It is concluded that SR-12813 inhibits cholesterol synthesis mainly by an enhanced degradation of HMG-CoA reductase. | en |
dc.format.extent | 7 | |
dc.language.iso | eng | |
dc.relation.ispartof | Journal of Biological Chemistry | |
dc.subject | Biochemistry | |
dc.title | The novel cholesterol-lowering drug SR-12813 inhibits cholesterol synthesis via an increased degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase | en |
dc.contributor.institution | Department of Human and Environmental Sciences | |
dc.contributor.institution | School of Life and Medical Sciences | |
dc.contributor.institution | Department of Pharmacy | |
dc.contributor.institution | Medicinal and Analytical Chemistry | |
dc.description.status | Peer reviewed | |
rioxxterms.versionofrecord | 10.1074/jbc.271.24.14376 | |
rioxxterms.type | Journal Article/Review | |
herts.preservation.rarelyaccessed | true | |