Effects of specific inhibition of sterol biosynthesis on the uptake and utilization of low density lipoprotein cholesterol by HepG2 cells.

Panini, S R; Gt, Everson; Spencer, T A

doi:10.1016/s0022-2275(20)41651-7

Cited by 14 publications

(2 citation statements)

References 40 publications

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“…Similar findings were also made upon incubation of CHO cells with labeled acetate in the presence of the decalin derivative (699). Subsequent studies (760) with the same compound inhibited the incorporation of Lesser amounts of 14 C were observed to be associated with "epoxycholesterol" and "desmosterol." These results were based on reverse-phase HPLC.…”

Section: E Formation Of 2425-epoxysterolssupporting

confidence: 63%

“…That the coordination of levels of HMG-CoA reductase activity and the LDL receptor activity is not invariant is indicated by a number of studies. Panini et al (760) reported that incubation of Hep G2 cells with 4,4,10␤trimethyl-trans-decal-3␤-ol (TMD; 20 g/ml), an inhibitor of the cyclization of 2,3-epoxysqualene, for 24 h in lipoprotein-deficient serum (after a preincubation of the cells for 24 h in the lipoprotein-deficient serum) had no significant effect on the levels of HMG-CoA reductase activity. However, incubation of the Hep G2 cells with the TMD at the same concentration under the same conditions resulted in increases in the levels of LDL binding, internalization, and degradation.…”

Section: Comparison Of the Potencies Of Selected Oxygenated Sterols On Binding To Aebs In Mcf7 Cells Inhibition Of Cell Growth Of Mcf7 Cementioning

confidence: 99%

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Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

Schroepfer

2000

Physiological Reviews

877

687

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Oxygenated derivatives of cholesterol (oxysterols) present a remarkably diverse profile of biological activities, including effects on sphingolipid metabolism, platelet aggregation, apoptosis, and protein prenylation. The most notable oxysterol activities center around the regulation of cholesterol homeostasis, which appears to be controlled in part by a complex series of interactions of oxysterol ligands with various receptors, such as the oxysterol binding protein, the cellular nucleic acid binding protein, the sterol regulatory element binding protein, the LXR nuclear orphan receptors, and the low-density lipoprotein receptor. Identification of the endogenous oxysterol ligands and elucidation of their enzymatic origins are topics of active investigation. Except for 24, 25-epoxysterols, most oxysterols arise from cholesterol by autoxidation or by specific microsomal or mitochondrial oxidations, usually involving cytochrome P-450 species. Oxysterols are variously metabolized to esters, bile acids, steroid hormones, cholesterol, or other sterols through pathways that may differ according to the type of cell and mode of experimentation (in vitro, in vivo, cell culture). Reliable measurements of oxysterol levels and activities are hampered by low physiological concentrations (approximately 0.01-0.1 microM plasma) relative to cholesterol (approximately 5,000 microM) and by the susceptibility of cholesterol to autoxidation, which produces artifactual oxysterols that may also have potent activities. Reports describing the occurrence and levels of oxysterols in plasma, low-density lipoproteins, various tissues, and food products include many unrealistic data resulting from inattention to autoxidation and to limitations of the analytical methodology. Because of the widespread lack of appreciation for the technical difficulties involved in oxysterol research, a rigorous evaluation of the chromatographic and spectroscopic methods used in the isolation, characterization, and quantitation of oxysterols has been included. This review comprises a detailed and critical assessment of current knowledge regarding the formation, occurrence, metabolism, regulatory properties, and other activities of oxysterols in mammalian systems.

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Section: E Formation Of 2425-epoxysterolssupporting

confidence: 63%

Section: Comparison Of the Potencies Of Selected Oxygenated Sterols On Binding To Aebs In Mcf7 Cells Inhibition Of Cell Growth Of Mcf7 Cementioning

confidence: 99%

Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

Schroepfer

2000

Physiological Reviews

877

687

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Approaches for the Design of Novel Anti-Atherogenic Compounds

Biessen

Sliedregt

Berkel

1997

Subcellular Biochemistry

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RPR 101821, a new potent cholesterol-lowering agent: inhibition of squalene synthase and 7-dehydrocholesterol reductase

Amin¹,

Rutledge²,

Needle³

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

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RPR 101821 (trans-2-[4-(benzoxazol-2-yl)-phenylmethoxy] amino cyclohexane hydrochloride) is a potent cholesterol-lowering agent in rodents and marmoset. The compound inhibited rat liver microsomal squalene synthase (IC50 = 1 nM) and 7-dehydrocholesterol (7DHC) reductase (IC50 = 1 microM; Lewis et al. 1995). When RPR 101821 (10 mg/kg), the 7DHC reductase inhibitor BM 15.766 (4[2-[4-(4-chlorocinnamyl)piperazine-1-yl]ethyl] benzoic acid; 10 mg/kg) or the HMG-CoA reductase inhibitor lovastatin (30 mg/kg) was given orally to rats at -29 h, -21 h and -5 h, serum cholesterol was reduced by 56%, 46% or 15%, respectively. The reduction in cholesterol with RPR 101821 was associated with an accumulation of 7DHC in serum, suggesting an inhibition of 7DHC reductase. In the presence of BM 15.766, RPR 101821 reduced the serum accumulation of 7DHC in a dose-dependent manner, with complete inhibition at 30 mg/kg, p.o. In Balb-cJ mice, RPR 101821 and lovastatin (50 mg/kg, b.i.d., p.o., for 14 days) lowered serum cholesterol by 67% and 2%, respectively. In marmosets, RPR 101821 and lovastatin (both at a dose of 10 mg/kg, p.o., b.i.d., for 7 days) reduced cholesterol by 28% and 19%, respectively. In summary, RPR 101821 is an orally effective potent cholesterol-lowering agent in rodents and a small primate species. The suggested mechanism of hypocholesterolemic effect is the inhibition of squalene synthase and 7DHC reductase.

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Effects of specific inhibition of sterol biosynthesis on the uptake and utilization of low density lipoprotein cholesterol by HepG2 cells.

Cited by 14 publications

References 40 publications

Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

Approaches for the Design of Novel Anti-Atherogenic Compounds

RPR 101821, a new potent cholesterol-lowering agent: inhibition of squalene synthase and 7-dehydrocholesterol reductase

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