| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Inhibition of hormone-stimulated steroidogenesis in cultured Leydig tumor cells by a cholesterol-linked phosphorothioate oligodeoxynucleotide antisense to diazepam-binding inhibitor Boujrad, N., J. R. Hudson, Jr., et al. (1993), Proc Natl Acad Sci U S A 90(12): 5728-31. Abstract: The polypeptide diazepam-binding inhibitor (DBI) has been previously shown to stimulate testicular Leydig, adrenocortical, and glial-cell mitochondrial steroidogenesis in vitro. To assess the in situ role of DBI in trophic hormone-stimulated steroidogenesis, we suppressed DBI levels in the hormone-responsive MA-10 Leydig tumor cells, using a cholesterol-linked phosphorothioate oligodeoxynucleotide (Chol-odN) antisense to DBI. Treating MA-10 cells with Chol-odN antisense to DBI resulted in a dose-dependent reduction of DBI levels (ED50 = 1 microM). In contrast, Chol-odN sense to DBI did not affect its expression. Saturating amounts of human choriogonadotropin (hCG) increased MA-10 progesterone production by 150-fold. Addition of increased concentrations of Chol-odNs sense to DBI or of a nonrelated sequence did not reduce the MA-10 response to hCG. However, in the presence of Chol-odN antisense to DBI that could reduce DBI levels, MA-10 cells lost their ability to respond to hCG (ED50 = 1 microM). In these studies the hCG-stimulated cAMP levels and cytochrome P450 side-chain cleavage activity, as measured by metabolism of 22(R)-hydroxycholesterol, were not affected by the Chol-odNs used. These observations provide unequivocal evidence that DBI plays a vital role in the acute stimulation of steroidogenesis by trophic hormones. |
| Inhibition of human vascular smooth muscle cell proliferation by lovastatin: the role of isoprenoid intermediates of cholesterol synthesis Munro, E., M. Patel, et al. (1994), Eur J Clin Invest 24(11): 766-72. Abstract: Restenosis remains the largest single obstacle to the long-term success of invasive vascular interventions. Lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce myointimal hyperplasia in animal models of restenosis and in one clinical coronary restenosis trial. We have assessed the effect of lovastatin on the growth of cultured human vascular smooth muscle cells derived from saphenous vein and vascular graft stenoses. Lovastatin (2 microM) inhibited proliferation over 14 days in saphenous vein (and graft stenoses) derived vascular smooth muscle cells by 42% and 32% respectively: this was not significantly different. Lovastatin (10 microM) reduced methyl 3H-thymidine uptake by 51% in saphenous vein-derived cells. These concentrations were significantly higher than those achieved in plasma during therapeutic dosage. Lovastatin-induced inhibition of vascular smooth muscle cell proliferation and methyl 3H-thymidine uptake was completely reversed by adding mevalonate (100 microM) but cholesterol (10-40 micrograms ml-1) had no effect. Isopentenyl adenine (25-50 microM) did not affect the inhibition of methyl 3H-thymidine uptake by lovastatin (10 microM), but farnesol (20 microM), another isoprenoid precursor of cholesterol synthesis, reversed the antiproliferative effect. |
| Inhibition of HUVEC tubulogenesis by hederacolchiside-A1 is associated with plasma membrane cholesterol sequestration and activation of the Ha-Ras/MEK/ERK cascade Barthomeuf, C., D. Boivin, et al. (2004), Cancer Chemother Pharmacol 54(5): 432-40. Abstract: PURPOSE: Neoangiogenesis is critical to cancer proliferation and metastasis and constitutes an attractive target for cancer therapy. It has previously been demonstrated that hederacolchiside-A1 (HCol-A1), a triterpenoid saponin from Hedera colchica Koch, has antimelanoma potential. The goal of this study was to evaluate, in vitro, if in addition to its tumoricidal effect on melanoma cells, HCol-A1 might affect endothelial cell network formation. METHODS: We investigated whether HCol-A1 affects matrigel-induced tubulogenesis and inhibits the viability (WST-1 assay) of human umbilical vein endothelial cells (HUVECs). To provide structure-activity relationships (SAR), studies were conducted on HCol-A1, oleanolic acid and hederacolchiside A (HCol-A), a triterpenoid saponin which possess the same sugar sequence as Hcol-A1. Plasma membrane cholesterol sequestration was studied by labelling with 3Hcholesterol and assayed with HCol-A1-cholesterol complexes. HCol-A1 signalling was investigated using immunoassays. RESULTS: In contrast to HCol-A and oleanolic acid, HCol-A1 inhibited matrigel-induced angiogenesis at micromolar concentration. Plasma membrane cholesterol sequestration was found to be critical for this activity. Activation of the Ras/MEK/ERK cascade appears to be one of the mechanisms by which Hcol-A1 affects HUVEC network formation. The predominant activation of the Ha-Ras isoform, which decreases HUVEC-tolerance to apoptosis, might contribute to the high susceptibility of this cell line to HCol-A1. CONCLUSION: Since cholesterol sequestration affects cell confluence-dependent remodelling of endothelial membranes and vascular endothelial growth factor receptor-2 activity, these results raise the possibility that Hcol-A1 might slow-down cancer proliferation and metastasis in vivo by inhibiting critical aspects of neoangiogenesis. Further in vivo studies are needed to verify this hypothesis. |
| Inhibition of ileal bile acid transport lowers plasma cholesterol levels by inactivating hepatic farnesoid X receptor and stimulating cholesterol 7 alpha-hydroxylase Li, H., G. Xu, et al. (2004), Metabolism 53(7): 927-32. Abstract: We investigated the effect of SC-435, a competitive inhibitor of ileal apical sodium-dependent bile acid cotransporter (ASBT) on ileal bile acid absorption and the hepatic nuclear receptor FXR (farnesoid X receptor), which regulates cholesterol 7 alpha-hydroxylase (CYP7A1) activity and mRNA levels. Eighteen New Zealand White (NZW) rabbits were divided into 2 groups: controls (n = 10) and fed SC-435 125 mg/kg/d for 1 week (n = 8). In rabbits treated with SC-435, fecal bile acid outputs increased by more than 8 times, reflecting substantial bile acid malabsorption. Plasma cholesterol levels decreased 26%, while bile acid pool sizes and biliary bile acid outputs did not change after treatment. CYP7A1 activity increased 64% and mRNA rose by 4 times after treatment. The expression of FXR target genes in the liver, short heterodimer partner (SHP) and bile salt export pump (BSEP), decreased 11.6 and 2.6 times, respectively, after treatment, which indicates inactivation of hepatic FXR. However, the mRNA levels of ileal bile acid binding protein (IBABP) did not change significantly, while ileal ASBT mRNA expression increased by 2.4 times after treatment. Rabbits treated with SC-435 developed ileal bile acid malabsorption, which decreased the return of bile acids (FXR ligands) to the liver to inactivate hepatic FXR, which upregulated CYP7A1 and lowered plasma cholesterol levels. Although fecal bile acid malabsorption was substantial, increased bile acid production from hepatic cholesterol kept biliary bile acid outputs intact. Thus, a new balance was reached in the liver, where increased bile acid synthesis compensated for diminished ileal bile acid absorption to maintain the circulating enterohepatic bile acid pool. |
| Inhibition of ileal Na+/bile acid cotransporter by S-8921 reduces serum cholesterol and prevents atherosclerosis in rabbits Higaki, J., S. Hara, et al. (1998), Arterioscler Thromb Vasc Biol 18(8): 1304-11. Abstract: The ileal Na+/bile acid cotransporter (IBAT) plays an important role in the enterohepatic circulation of bile acids. We investigated the effects of IBAT inhibition on the maintenance of serum cholesterol level by using a novel IBAT inhibitor, S-8921, in rabbits. Administration of S-8921 by its incorporation into the diet (0.01% to 0.1%) for 1 to 2 weeks in heterozygous Watanabe heritable hyperlipidemic rabbits decreased serum cholesterol by 29% to 37% and increased fecal excretion of measured bile acids by 60% to 180% compared with control rabbits. Liver microsomal cholesterol 7alpha-hydroxylase and 3-hydroxy-3-methylglutaryl coenzyme A reductase activities were increased by 75% to 84% and 84% to 89%, respectively, with S-8921 treatment. S-8921 administration (0.1% in the diet) to normal New Zealand White rabbits for 2 weeks resulted in increased hepatic low density lipoprotein receptor expression, which was assessed by Northern blot analysis. In cholesterol-fed New Zealand White rabbits, S-8921 treatment (0.003% to 0.1% in the diet) for 10 weeks dose-dependently inhibited the development of hypercholesterolemia. It also inhibited the accumulation of cholesterol in the aortic arch and reduced the severity of coronary atherosclerosis. These results indicate that IBAT inhibition by S-8921 affects serum cholesterol, liver enzymes, low density lipoprotein receptor activity, and atherosclerosis in the same manner as bile acid sequestrants. We suggest that an IBAT inhibitor such as S-8921 could be useful in the treatment of hypercholesterolemia. |
| Inhibition of intestinal cholesterol absorption by ezetimibe in humans Sudhop, T., D. Lutjohann, et al. (2002), Circulation 106(15): 1943-8. Abstract: BACKGROUND: Ezetimibe has been shown to inhibit cholesterol absorption in animal models, but studies on cholesterol absorption in humans have not been performed thus far. METHODS AND RESULTS: The effect of ezetimibe (10 mg/d) on cholesterol absorption and synthesis, sterol excretion, and plasma concentrations of cholesterol and noncholesterol sterols was investigated in a randomized, double-blind, placebo-controlled, crossover study in 18 patients with mild to moderate hypercholesterolemia. Treatment periods lasted 2 weeks with an intervening 2-week washout period. Fractional cholesterol absorption rates averaged 49.8+/-13.8% on placebo and 22.7+/-25.8% on ezetimibe, indicating a reduction of 54% (geometric mean ratio; P< 0.001). Cholesterol synthesis increased by 89% from 931+/-1027 mg/d on placebo to 1763+/-1098 mg/d on ezetimibe (P<0.001), while the ratio of lathosterol-to-cholesterol, an indirect marker of cholesterol synthesis, was increased by 72% (P<0.001). Bile acid synthesis was insignificantly increased (placebo: 264+/-209 mg/d, ezetimibe: 308+/-184 mg/d; P=0.068). Mean percent changes from baseline for LDL and total cholesterol after ezetimibe treatment were -20.4% and -15.1%, respectively (P<0.001 for both), whereas campesterol and sitosterol were decreased by -48% and - 41%, respectively. CONCLUSION: In humans, ezetimibe inhibits cholesterol absorption and promotes a compensatory increase of cholesterol synthesis, followed by clinically relevant reductions in LDL and total cholesterol concentrations. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols sitosterol and campesterol, suggesting an effect on the absorption of these compounds as well. |
| Inhibition of intestinal cholesterol absorption by surfomer (alpha-olefin maleic acid) affects hepatic cholesterol synthesis and low density lipoprotein transport in hamsters fed a fat-enriched diet Bertolotti, M. and D. K. Spady (2001), Dig Liver Dis 33(2): 145-50. Abstract: BACKGROUND: Surfomer (alpha-olefin maleic acid) reduces intestinal cholesterol absorption. AIMS: This study was performed to investigate the effect of surfomer on cholesterol synthesis and low density lipoprotein in hamsters fed a hypercholesterolaemic, lipid-enriched diet. ANIMALS AND METHODS: Male hamsters were fed a diet enriched in cholesterol (0.07%) and saturated fatty acids (coconut oil 20%); the diet was supplemented with 3% surfomer, for 1-4 weeks. Cholesterol synthesis was assessed measuring incorporation of 3Hwater into tissue sterols; low density lipoprotein clearance was determined using a primed-continuous infusion of (125I)tyramine-cellobiose lipoprotein. RESULTS: Cholesterol synthesis was suppressed after 3 weeks of hyperlipidaemic diet in liver and small bowel (by 88% and 38%, respectively) and was significantly increased by supplementing the fat-enriched diet with surfomer. Low density lipoprotein-cholesterol was increased by 44% after 4 weeks of hyperlipidaemic diet, in parallel with a decrease in hepatic low density lipoprotein clearance rates (48+/-3 vs 68+/-7 microl of plasma/h per g of tissue). Concurrent treatment with surfomer for 1, 2 or 4 weeks prevented the decrease of clearance and maintained normal low density lipoprotein-cholesterol levels at all time points. CONCLUSIONS: Surfomer represents a powerful tool to investigate the impact of cholesterol absorption on sterol homeostasis. Furthermore, since surfomer appears to normalize low density lipoprotein transport in hamsters fed a diet comparable to a lipid-rich "western-style" regimen, this drug may deserve consideration as an adjunct treatment for hypercholesterolaemia in selected patient groups. |
| Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells Runz, H., J. Rietdorf, et al. (2002), J Neurosci 22(5): 1679-89. Abstract: Generation of amyloid-beta (Abeta) from the amyloid precursor protein (APP) requires proteolytic cleavage by two proteases, beta- and gamma-secretase. Several lines of evidence suggest a role for cholesterol on secretase activities, although the responsible cellular mechanisms remain unclear. Here we show that alterations in cholesterol transport from late endocytic organelles to the endoplasmic reticulum have important consequences for both APP processing and the localization of gamma-secretase-associated presenilins (PS). Exposure of neuronal cells to cholesterol transport-inhibiting agents resulted in a marked decrease in beta-cleavage of full-length APP. In contrast, gamma-secretase activity on APP C-terminal fragments was enhanced, increasing the production of both Abeta40 and Abeta42. Remarkably, retention of cholesterol in endosomal/lysosomal compartments induced PS1 and PS2 to accumulate in Rab7-positive vesicular organelles implicated in cholesterol sorting. Accumulation of PS in vesicular compartments was prominent in both Chinese hamster ovary cells deficient in Niemann-Pick C1 protein as well as in neuronal cells exposed to the cholesterol transport-inhibiting agent U18666A. Because Abeta42 also localized to PS1-containing vesicular compartments, organelles involved in cholesterol transport might represent an important site for gamma-secretase activity. Our results suggest that the subcellular distribution of cholesterol may be an important factor in how cholesterol alters Abeta production and the risk of Alzheimer's disease. |
| Inhibition of lecithin cholesterol acyltransferase by phosphatidylcholine hydroperoxides Davit-Spraul, A., P. Therond, et al. (1999), FEBS Lett 447(1): 106-10. Abstract: To gain insight into the nature of the lecithin-cholesterol acyltransferase inhibitory factor(s), we separated and collected the oxidation products from oxidized lipoproteins after lipoxygenase treatment. Isolated fractions identified by chemiluminescence, as hydroperoxides of phosphatidylcholine, were found to produce a significant reduction of lecithin-cholesterol acyltransferase activity. The reaction kinetics of lecithin-cholesterol acyltransferase with reconstitued high density lipoproteins were studied in the presence of 0.6 and 1.2 microM hydroperoxides of phosphatidylcholine. No significant changes in the apparent Vmax were observed but a concentration-dependent increase in slope of the reciprocal plots and in the apparent Km values was observed with increasing hydroperoxide concentrations. These results show that the active site of lecithin-cholesterol acyltransferase is not affected by the presence of phosphatidylcholine hydroperoxides. Nevertheless, hydroperoxides of phosphatidylcholine altered the reactivity of lecithin-cholesterol acyltransferase for reconstitued high density lipoproteins suggesting either an alteration of the binding of lecithin-cholesterol acyltransferase to the reconstitued high density lipoproteins or a competitive inhibition mechanism. |
| Inhibition of lipid peroxidation and cholesterol levels in mice by curcumin Soudamini, K. K., M. C. Unnikrishnan, et al. (1992), Indian J Physiol Pharmacol 36(4): 239-43. Abstract: Effect of oral administration of curcumin (diferuloyl methane) on lipid peroxidation in various organs of mice like liver, lung, kidney and brain was studied in control animals as well as those given carbon tetrachloride, paraquat and cyclophosphamide. Oral administration of curcumin significantly lowered the increased peroxidation of lipids in these tissues produced by these chemicals. Administration of curcumin was also found to lower significantly the serum and tissue cholesterol levels in these animals, indicating that the use of curcumin helps in conditions associated with peroxide induced injury such as liver damage and arterial diseases. |
| Inhibition of lipoprotein lipase induced cholesterol ester accumulation in human hepatoma HepG2 cells Cianflone, K., R. K. Avramoglu, et al. (1996), Atherosclerosis 120(1-2): 101-14. Abstract: It has been suggested previously that lipoprotein lipase may act as a ligand to enhance binding and uptake of lipoprotein particles. In the present study we have examined the capacity of bovine milk lipoprotein lipase to induce intracellular accumulation of triglyceride and cholesterol ester by VLDL (Sr 60-400) isolated from Type IV hypertriglyceridemic subject (HTg-VLDL) in HepG2 cells, independent of its lipolytic activity. We have also attempted to elucidate the cellular receptor mechanisms responsible for these effects. HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester were dependent on the presence of an active lipase. Bovine milk lipoprotein lipase (LPL) increases triglyceride mass by 301% +/- 28% (P < 0.0005) and cholesterol ester mass by 176% +/- 12% (P < 0.0005). These HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester did not occur when heat-inactivated lipase was used. Rhizopus lipase could replace LPL and cause equivalent increases in intracellular triglyceride and cholesterol ester (472% +/- 61%(P < 0.005) and 202% +/- 25% (P < 0.025) respectively vs. control). HTg-VLDL treated with LPL and reisolated also caused equivalent increases (274% +/- 18%(P < 0.01) and 177% +/- 12% (P < 0.005) for triglyceride and cholesterol ester). LDL also caused increases in intracellular cholesterol ester (189% +/- 20%(P < 0.005)), although three times more LDL cholesterol had to be added to achieve the same effect. These LDL-induced increases were effectively blocked by monoclonal antibodies directed against the B,E receptor binding domains of apo B (-97% +/- 13% (P < 0.0005) with anti-apo B 5E11 and -68% +/- 13% (P < 0.05) for anti-apo B B1B3) or by anti-B,E receptor antibodies (-77% +/- 7% (P < 0.01) antibody C7). These same antibodies had little effect on the HTg-VLDL+LPL-induced increases in cholesterol ester (+21%, +15% and -22% for 5E11, B1B3 and C7, respectively). Monoclonal anti-apo E antibodies also had no effect on LDL-mediated increases in intracellular cholesterol ester, but had a small and significant effect on VLDL-mediated increases in cholesterol ester. However, heparin, which interferes with cell surface proteoglycan interaction, was very effective at blocking HTg-VLDL-mediated increases in cholesterol ester in the presence of LPL (-86% +/- 8% P < 0.0005). Heparin was also effective in the presence of Rhizopus lipase (-79%) or lipolyzed re-isolated HTg-VLDL (-95%). These results suggest that lipoprotein lipase may enhance the uptake process beyond its role in lipolytic remodelling but does not appear to be an absolute requirement. In contrast, heparin had no effect on LDL-mediated cholesterol ester accumulation. Lactoferrin, which inhibits interaction with the low density lipoprotein receptor-related protein (LRP), was also very effective at inhibiting HTg-VLDL increases in intracellular cholesterol ester (-95% +/- 6%, P < 0.01). However, there was no effect of either heparin or lactoferrin on HTg-VLDL-mediated triglyceride accumulation. Thus cell surface heparin sulphate may facilitate intracellular lipid acquisition by providing a stabilizing bridge with the lipoproteins and enhance uptake through receptor-mediated processes such as LRP. |
| Inhibition of lysophospholipase by cholesterol in rabbit aorta Miyake, R., M. Yokoyama, et al. (1990), Biochem Biophys Res Commun 167(1): 143-7. Abstract: Lysophospholipase activity was measured in rabbit aorta using 1-1-14Cpalmitoyl-sn-glycero-3-phosphocholine as a substrate. The enzyme did not require Ca2+ for its activation and the maximal activation was attained in the presence of EGTA. Cholesterol dose-dependently inhibited the lysophospholipase activity in the soluble fraction and IC50 value was approximately 15 microM. Lineweaver-Burk plot revealed that cholesterol competitively inhibited lysophospholipase and Km values in the presence and absence of cholesterol (15.5 microM) were 12.3 and 2.8 microM, respectively. Vmax values were approximately 475 pmol/min.mg. The results suggest that cholesterol can interact with the enzyme per se, resulting in the inhibition of the lysophospholipase activity in rabbit aorta. |
| Inhibition of membrane-associated methyltransferases by a cholesterol-based metal chelator Hodges, H. B., M. Zhou, et al. (2005), Bioconjug Chem 16(3): 490-3. Abstract: We have designed, synthesized, and characterized a metal chelating compound that is based on the structure of cholesterol and contains the high affinity metal chelating group, lysine nitrilotriacetic acid (Lys-NTA). Using the enzyme isoprenylcysteine carboxylmethyltransferase (Icmt) from yeast as a model integral membrane metalloenzyme, we find that this agent potently inhibits Icmt activity with an IC(50) value between 35 and 75 microM, which is at least 40 times more potent than the best known Icmt metal chelating inhibitor, Zincon. We propose that the rigid hydrophobic cholesterol moiety promotes partitioning into the membrane, enabling the metal-binding NTA group(s) to inactivate the enzyme by metal chelation. Because this compound is based on a naturally occurring membrane lipid and appears to chelate metals buried deeply within water insoluble environments, this agent may also be useful as a general tool for identifying previously unappreciated metal dependencies of other classes of membrane proteins. |
| Inhibition of mitochondrial cholesterol side-chain cleavage by structural analogs of cholesterol sulfate Robertson, D. G., D. Perry, et al. (1991), Endocr Res 17(1-2): 297-306. Abstract: Cholesterol sulfate inhibits cholesterol side-chain cleavage in adrenal mitochondria. In this study, analogs of cholesterol sulfate were evaluated for their ability to inhibit steroidogenesis. Structural requirements for inhibitory activity included a planar A-B ring junction, an intact side chain, and a 3 beta-ester group containing a single negative charge. This structural specificity argues against cholesterol sulfate acting solely as a membrane perturbing agent or a detergent, and also differs in some features from the specificity for binding to cytochrome P-450scc. |
| Inhibition of N-methyl-N-nitrosourea- and 7,12-dimethylbenza anthracene-induced rat mammary tumorigenesis by dietary cholesterol is independent of Ha-Ras mutations El-Sohemy, A. and M. C. Archer (2000), Carcinogenesis 21(4): 827-31. Abstract: Dietary cholesterol has previously been shown to inhibit rat mammary tumorigenesis but the mechanisms remain unclear. Uptake of serum low density lipoprotein cholesterol by tissues leads to down-regulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate limiting enzyme in cholesterol biosynthesis that catalyzes the formation of mevalonate. In addition to being a precursor of cholesterol, mevalonate is necessary for DNA synthesis and cell proliferation. Isoprenoids, also derived from mevalonate, are required for the post-translational modification of Ras proteins that are mutated in a number of carcinogen-induced rat mammary tumors. The purpose of this study, therefore, was to determine whether inhibition of tumorigenesis by cholesterol is dependent on the frequency of mutations in the Ha-ras gene. Female Sprague-Dawley rats (30/group) were given a single dose of either N-methyl-N-nitrosourea (MNU, 50 mg/kg i.p.) or 7, 12-dimethylbenzaanthracene (DMBA, 100 mg/kg intragastrally), carcinogens that produce tumors with either a high (MNU) or low (DMBA) frequency of Ha-ras mutations in codon 12 or 61, respectively. Rats were fed either a control AIN-93G diet or the control diet supplemented with 0.3% cholesterol for 14 weeks. Dietary cholesterol significantly decreased the final tumor incidence in rats given DMBA (83 versus 100%, P < 0.05) or MNU (53 versus 77%, P < 0.05). HMG-CoA reductase activity was higher in mammary tumors than in normal mammary glands, but the activity of this enzyme was reduced by cholesterol feeding only in mammary glands and not in tumors. Tumors induced by MNU had a high frequency of Ha-ras mutations in both the control (65%) and cholesterol-fed (68%) groups. Tumors induced by DMBA had a low frequency of Ha-ras mutations that also did not differ between the control (21%) and cholesterol-fed (18%) groups. These findings show that dietary cholesterol inhibits mammary tumorigenesis induced by either MNU or DMBA and that the inhibition is independent of the type or extent of mutations in the Ha-ras gene. |
| Inhibition of pancreatic cholesterol esterase reduces cholesterol absorption in the hamster Heidrich, J. E., L. M. Contos, et al. (2004), BMC Pharmacol 4: 5. Abstract: BACKGROUND: Pancreatic cholesterol esterase has three proposed functions in the intestine: 1) to control the bioavailability of cholesterol from dietary cholesterol esters; 2) to contribute to incorporation of cholesterol into mixed micelles; and 3) to aid in transport of free cholesterol to the enterocyte. Inhibitors of cholesterol esterase are anticipated to limit the absorption of dietary cholesterol. RESULTS: The selective and potent cholesterol esterase inhibitor 6-chloro-3-(1-ethyl-2-cyclohexyl)-2-pyrone (figure 1, structure 1) was administered to hamsters fed a high cholesterol diet supplemented with radiolabeled cholesterol ester. Hamsters were gavage fed 3H-labeled cholesteryl oleate along with inhibitor 1, 0-200 micromoles. Twenty-four hours later, hepatic and serum radioactive cholesterol levels were determined. The ED50 of inhibitor 1 for prevention of the uptake of labeled cholesterol derived from hydrolysis of labeled cholesteryl oleate was 100 micromoles. The toxicity of inhibitor 1 was investigated in a 30 day feeding trial. Inhibitor 1, 100 micromoles or 200 micromoles per day, was added to chow supplemented with 1% cholesterol and 0.5% cholic acid. Clinical chemistry urinalysis and tissue histopathology were obtained. No toxicity differences were noted between control and inhibitor supplemented groups. CONCLUSIONS: Inhibitors of cholesterol esterase may be useful therapeutics for limiting cholesterol absorption. |
| Inhibition of plasma cholesterol ester hydroperoxide and phosphatidylcholine hydroperoxide formation as measures of antioxidant status Noguchi, N. and E. Niki (1997), Methods Enzymol 282: 271-8. |
| Inhibition of prostaglandin synthesis fails to prevent gallbladder mucin hypersecretion in the cholesterol-fed prairie dog O'Leary, D. P., W. W. LaMorte, et al. (1991), Gastroenterology 101(3): 812-20. Abstract: Gallstone formation in the cholesterol-fed prairie dog is preceded by an increase in mucin secretion by the gallbladder epithelium, and mucin hypersecretion is believed to promote cholesterol gallstone formation by accelerating the nucleation of cholesterol monohydrate crystals. Some studies have suggested that gallbladder mucin hypersecretion is mediated by increases in gallbladder prostaglandin synthesis, but other observations are difficult to reconcile with this view. An organ culture technique was used to measure mucin secretion in normal prairie dog gallbladder in response to exogenous prostaglandins and agents that increased or decreased endogenous prostaglandin production. Incubation with indomethacin produced a concentration-dependent inhibition of endogenous prostaglandin synthesis with virtually complete inhibition at 10(-5) mol/L indomethacin. However, indomethacin had no effect on gallbladder mucin secretion at concentrations as high as 10(-5) mol/L, and significant inhibition of mucin secretion was only found at 10(-4) mol/L indomethacin, a concentration that also produced a significant increase in lactate dehydrogenase release from cultured explants. Incubation of gallbladder explants with the calcium ionophore A23187 significantly stimulated endogenous prostaglandin synthesis in a concentration-dependent manner, increasing synthesis of prostaglandins E and F to as much as 278% +/- 20% and 335% +/- 21% of basal values, respectively; however, the same concentrations of A23187 did not stimulate mucin secretion. Incubation of gallbladder explants in the presence of exogenous prostaglandin E2 or prostaglandin F2a in concentrations as high as 10(-6) mol/L also did not stimulate mucin secretion. Prairie dogs fed a lithogenic 1.2% cholesterol diet showed a significant increase in gallbladder mucin secretion after 1 week (117.5 +/- 10.2% of control, P less than 0.05), and 4 of 5 had formed cholesterol monohydrate crystals after 3 weeks. Long-term treatment with indomethacin, 1.2 mg.kg-1.day-1, failed to inhibit gallbladder mucin hypersecretion (129.2 +/- 10.7% of control after 1 week) or cholesterol monohydrate crystal formation (3/5) in cholesterol-fed prairie dogs. Furthermore, incubation of explants with 10(-5) mol/L indomethacin failed to prevent in vitro mucin hypersecretion in cholesterol-fed animals. These findings suggest that prostaglandins do not regulate gallbladder mucin secretion in the prairie dog, and it is unlikely that increases in gallbladder prostaglandin synthesis are responsible for mediating gallbladder mucin hypersecretion during cholelithiasis in the prairie dog. |
| Inhibition of protein tyrosine kinase alters the effect of serum basic protein I on triacylglycerols and cholesterol differently in normal and hyperapoB fibroblasts Kwiterovich, P. O., Jr. and M. Motevalli (1995), Arterioscler Thromb Vasc Biol 15(8): 1195-203. Abstract: We studied whether the stimulatory effect of human serum basic protein I (BP I) on the formation of cell triacylglycerols and cholesterol may be mediated through protein tyrosine kinase in normal fibroblasts, and whether there was a deficiency in such a process in cells from subjects with hyperapobetalipoproteinemia (hyperapoB). Genistein, a highly specific inhibitor of tyrosine kinase phosphorylation, was used as a probe. When BP I (428.0 nmol/L) alone was added to F-12 medium without genistein, the mean mass of cell triacylglycerols doubled in six normal cell lines from healthy subjects, an effect that was decreased by 50% in six cell lines from subjects with hyperapoB (P =.007). The addition of genistein with BP I to normal cells decreased the stimulation of triacylglycerol formation by BP I by about 50% (P =.008), whereas genistein had little effect in the BP I-treated hyperapoB cells. The effect of genistein on the stimulation of triglyceride and cholesterol production by BP I was shown to be both time and concentration (92.5 nmol/mL medium nadir) dependent. In normal fibroblasts. BP I stimulated the rate of incorporation of both 14Cacetate (P =.0001) and 3Hmevalonolactone (P =.002) into unesterified cholesterol, an effect that was markedly deficient in the hyperapoB cells (P =.0001 for 14Cacetate and P =.0002 for 3Hmevalonolactone). In normal but not hyper-apoB cells, genistein inhibited the significant stimulation by BP I of the rates of both 14Cacetate (P =.0001) and 3Hmevalonolactone (P =.04) incorporation into unesterified cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Inhibition of rat mammary tumorigenesis by dietary cholesterol el-Sohemy, A., W. R. Bruce, et al. (1996), Carcinogenesis 17(1): 159-62. Abstract: The effects of dietary cholesterol and oxidized cholesterol on mammary tumor development were examined in female Sprague-Dawley rats exposed to the carcinogen N-methyl-N-nitrosourea (MNU). Animals were administered 50 mg/kg MNU at 50 days of age and fed either a control (AIN-76) diet or the control diet supplemented with 0.3% cholesterol or 0.3% oxidized cholesterol for up to 26 weeks. The oxidized cholesterol was prepared by heating cholesterol at 110 degrees C for 48 h. Gas chromatographic analysis of the oxidized cholesterol revealed a 2% yield of oxidation products in addition to a large amount of unchanged cholesterol (> 96%). Tumor incidence in the cholesterol group (67%) was significantly lower than in the control group (96%, P < 0.05), but the oxidized cholesterol group (79%) was not significantly different from the control or cholesterol groups. Average number of tumors per animal was lower in the cholesterol group (1.5) than in the control (2.8) or oxidized cholesterol groups (2.3, P < 0.005). Serum low density lipoprotein (LDL) cholesterol was greater in the cholesterol (185 +/- 38 mg/dl) and the oxidized cholesterol groups (160 +/- 34 mg/dl) than in the controls (55 +/- 4 mg/dl, P < 0.05), although there was no difference between the cholesterol and the oxidized cholesterol groups. These results show that dietary cholesterol inhibits mammary tumor development in this model. Elevated serum LDL cholesterol may inhibit de novo cholesterol synthesis in preneoplastic and/or tumor cells, thereby inhibiting their proliferation. |