Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and cholesterol biosynthesis by oxylanosterols.

Panini, Sankhavaram R.; Sexton, Russell C.; Gupta, A.; Parish, Edward J.; Chitrakorn, Sarawanee; Rudney, Harry

doi:10.1016/s0022-2275(20)38755-1

Cited by 62 publications

(13 citation statements)

References 39 publications

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“…Inspection of their results indicates IC 50 values of ϳ25 M in the hepatocytes and ϳ1 M in the CHO-K1 cells. In the intestinal epithelial cells, the IC 50 value was reported to be 0.24 M by the same investigators (758). In the latter cells, lanost-8-ene-3␤,25-diol and its 3-keto derivative showed IC 50 values of 0.1 and 0.3 M, respectively.…”

Section: B Effects Of Oxysterols On Hmg-coa Reductase In Cultured Cellsmentioning

confidence: 88%

“…(24S)-24,25-Epoxylanosterol lowered the levels of HMG-CoA reductase in mouse L cells (1102), rat intestinal epithelial cells (361,758), rat hepatocytes (757), and CHO-K1 cells (757). The 24S-isomer appeared to be more potent than the 24R-sterol in lowering reductase activity in mouse L cells (1102); however, the reported variation precludes a more definitive statement.…”

Section: B Effects Of Oxysterols On Hmg-coa Reductase In Cultured Cellsmentioning

confidence: 99%

“…The 24R-and 24S-isomers of 24,25-epoxy-Chol and of 24,25-epoxylanosterol are resistant to separation by capillary GC as their acetate derivatives (280) or by reversephase HPLC on routine C 18 columns (280,758,759) either as the free sterols or their acetate derivatives. However, these isomers are separable on a special Vydac C 18 column (280,759).…”

Section: Chromatographic Separations Of Oxysterol Isomersmentioning

confidence: 99%

“…Corsini et al (218) reported that 26-OH-Chol and 25-OH-Chol had no effect on HMG-CoA reductase activity when added to cell-free extracts of rat arterial smooth muscle cells. Panini et al (758) observed that (24S)-24,25-epoxylanosterol, lanost-8ene-3␤,25-diol, and 25-hydroxylanost-8-en-3-one had no effect on HMG-CoA reductase activity when added directly to cell-free extracts of intestinal epithelial (IEC-6) cells, whereas each showed significant potency in lowering reductase activity when incubated with the cells. Direct addition of 3␤-hydroxy-5␣-cholest-8( 14)-en-15-one (100 M) to rat liver microsomes under a variety of conditions had no effect on the levels of HMG-CoA reductase activity (649).…”

Section: Effects Of Direct Addition Of Oxysterols To Microsomes and Cell-free Preparationsmentioning

confidence: 99%

“…Characterization of the various products was limited to their behavior on HPLC. Panini et al(758) studied the metabolism of the 24S-isomer of 24,25-epoxylanosterol by cultured intestinal epithelial (IEC-6) cells.3 H-labeled (24S)-24,25-epoxylanosterol was prepared by incubation of IEC-6 cells with [ 3 H]acetate in the presence of U-18666A (to cause the accumulation of labeled 2,3: 22,23-diepoxysqualene) followed by further incubation of the cells with fresh medium containing ketoconazole to inhibit the metabolism of the 24,25-epoxylanosterol. Incubation of the IEC-6 cells with the biosynthetically labeled (24S)-24,25-[ 3 H]epoxylanosterol resulted in the formation of (24S)-24,25-epoxy-Chol, as judged by reverse-phase HPLC and lithium aluminum hydride reduction of the product to material with the mobility of 25-OH-Chol on reverse-phase HPLC.…”

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confidence: 99%

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Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

Schroepfer

2000

Physiological Reviews

872

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: B Effects Of Oxysterols On Hmg-coa Reductase In Cultured Cellsmentioning

confidence: 88%

Section: B Effects Of Oxysterols On Hmg-coa Reductase In Cultured Cellsmentioning

confidence: 99%

Section: Chromatographic Separations Of Oxysterol Isomersmentioning

confidence: 99%

Section: Effects Of Direct Addition Of Oxysterols To Microsomes and Cell-free Preparationsmentioning

confidence: 99%

mentioning

confidence: 99%

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Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

Schroepfer

2000

Physiological Reviews

872

687

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Cellular toxicity of oxycholesterols

et al. 2006

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Oxycholesterols (OS) are formed from cholesterol or its immediate precursors by enzymatic or free radical action in vivo, or they may be derived from food. OS exhibit a wide spectrum of biological activities. In OS cytotoxicity, several mechanisms seem to be involved: e.g. inhibition of HMG-CoA reductase activity, antiproliferative action, apoptosis induction, replacement of cholesterol by OS in membranes followed by changes in cellular membrane structure and functionality, and immune system functions alteration. Furthermore, OS may be mutagenic and carcinogenic and may serve as intracellular signaling or regulatory molecules. Here we review OS cellular activities with special attention to the cytotoxic action in vivo and in vitro using experimental models.

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Potential role of nonstatin cholesterol lowering agents

et al. 2011

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SummaryAlthough statins, 3b-hydroxy-3b-methylglutaryl coenzyme A reductase (HMGR) inhibitors, have revolutionized the management of cardiovascular diseases by lowering serum low density lipoproteins, many patients suffer from their side effects. Whether the statin side effects are related to their intrinsic toxicity or to the decrease of HMGR main isoprenoid end products, which are essential compounds for cell viability, is still debated. In addition to HMGR, the key and rate limiting step of cholesterol synthesis, many enzymes are involved in this multi-step pathway whose inhibition could be taken into account for a ''nonstatin approach'' in the management of hypercholesterolemia. In particular, due to their unique position downstream from HMGR, the inhibition of squalene synthase, farnesyl diphosphate farnesyltransferase (FDFT1), squalene epoxidase (SQLE), and oxidosqualene cyclase:lanosterol synthase (OSC) should decrease plasma levels of cholesterol without affecting ubiquinone, dolichol, and isoprenoid metabolism. Thus, although FDFT1, SQLE and OSC are little studied, they should be considered as perspective targets for the development of novel drugs against hypercholesterolemia. Here, structurefunction relationships of FDFT1, SQLE, and OSC are reviewed highlighting the advantages that the downstream inhibition of HMGR could provide when compared to the statin-based therapy.2011 IUBMB IUBMB Life, 63(11): 964-971, 2011

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Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and cholesterol biosynthesis by oxylanosterols.

Cited by 62 publications

References 39 publications

Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

Cellular toxicity of oxycholesterols

Potential role of nonstatin cholesterol lowering agents

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