| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Effects of simvastatin on bone regeneration in the mandibles of ovariectomized rats and on blood cholesterol levels Junqueira, J. C., M. N. Mancini, et al. (2002), J Oral Sci 44(3-4): 117-24. Abstract: The purpose of this study was to evaluate the effects of simvastatin on guided bone regeneration in the mandibles of ovariectomized rats, and to observe their blood cholesterol levels. Seventy female rats were divided into two groups: control and treated, both groups containing normal and ovariectomized rats. A month after ovariectomy a bone defect was created in the mandible, and was covered by a polytetrafluoroethylene membrane. The treated groups received simvastatin orally for 15 or 30 days. The rats were sacrificed 15, 30 or 60 days after surgery, at which time a blood sample was extracted for blood cholesterol level analysis and the mandible was extracted for densitometric, histological and morphometric analysis. All specimens underwent analysis of variance. The ovariectomized animals had higher cholesterol levels than the treated normal animals, and no significant difference was found between the different treatment periods and the sacrifice times. The densitometric, histological and morphometric analysis showed that the treated ovariectomized animals developed more new bone than the control ovariectomized rats, but no significant difference was observed between the treatment periods. It can be concluded that the deficiency of estrogen increased the level of blood cholesterol and that the simvastatin aided new bone formation in the ovariectomized animals. |
| Effects of simvastatin on hepatic cholesterol metabolism, bile lithogenicity and bile acid hydrophobicity in patients with gallstones Smith, J. L., P. D. Roach, et al. (2000), J Gastroenterol Hepatol 15(8): 871-9. Abstract: BACKGROUND AND AIMS: There is limited information available on the effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on hepatic and biliary cholesterol metabolism in patients with gallstones. The aims of this study were to determine the effect of simvastatin on the regulatory elements of cholesterol metabolism that determine the concentrations of cholesterol in plasma and bile. METHODS: Thirty-one gallstone patients were enrolled in the study; 17 were treated with 20 mg simvastatin daily for 3 weeks prior to cholecystectomy and 14 served as controls. Samples of blood, liver, gall-bladder bile and bile from the common bile duct (CBD) were collected and analysed. RESULTS: The plasma cholesterol (-30%), triacylglycerol (-23%) and low-density lipoprotein (LDL) cholesterol (-42%) concentrations were significantly lowered by simvastatin treatment, as was the plasma lathosterol: cholesterol (-70%), which reflects whole-body cholesterol synthesis. Despite these changes, the hepatic LDL receptor protein and LDL receptor activity in circulating mononuclear cells were similar in both groups. There were no differences in the plasma phytosterol: cholesterol, which reflects the intestinal cholesterol absorption capacity or in the activity of hepatic acyl-coenzyme A: cholesterol acyltransferase. There were however, lower cholesterol concentrations in CBD (-68%) and gall bladder (-41%) bile, and decreased lithogenic (-47%) and bile acid hydrophobicity (-22%) indices of CBD bile in the simvastatin group. CONCLUSIONS: These data indicate that simvastatin reduced plasma and biliary cholesterol levels primarily by reducing cholesterol synthesis. The reduction in CBD bile lithogenicity and bile acid hydrophobicity by simvastatin suggests that this agent may be useful for people who have early stages of cholesterol gallstone development and in whom a choleretic effect is required. |
| Effects of simvastatin on liver and plasma levels of cholesterol, dolichol and ubiquinol in hypercholesterolemic rats Marinari, U. M., M. A. Pronzato, et al. (1995), Ital J Biochem 44(1): 1-9. Abstract: Increased levels of blood cholesterol are considered as a major factor in the development of atherosclerosis. Simvastatin, a drug which blocks hydroxymethylglutaryl coenzyme A reductase (HMGCoAR), reduces plasma cholesterol and increases HDL-cholesterol in rats fed a hypercholesterolemic diet. Moreover, simvastatin produces a significant decrease of ubiquinol and dolichol in plasma and in liver. |
| Effects of simvastatin on plasma lipoprotein subfractions, cholesterol esterification rate, and cholesteryl ester transfer protein in type II hyperlipoproteinemia Homma, Y., H. Ozawa, et al. (1995), Atherosclerosis 114(2): 223-34. Abstract: We investigated the effects of simvastatin on plasma levels of lipoprotein subfractions, cholesterol esterification rates and activities of cholesteryl ester transfer protein in 28 patients with type II hyperlipoproteinemia (i.e., nonfamilial hyperlipoproteinemia type IIa and type IIb, and heterozygous familial hypercholesterolemia (FH)). Plasma levels of VLDL-cholesterol (C) and VLDL-triglyceride (TG) were significantly reduced overall by 12.9 +/- 58.0% (mean +/- S.D.; P < 0.05) and 4.2 +/- 54.2% (P < 0.05) respectively, but not in FH. Plasma levels of IDL-C and IDLT-G were decreased overall by 23.2 +/- 47.5% (P < 0.001) and 12.3 +/- 49.7% (P < 0.05), respectively, again mainly due to decreases seen in nonfamilial type II hyperlipoproteinemia. Plasma levels of LDL1 (1.019 < d < 1.045)-C and LDL1-TG were significantly reduced by 33.1 +/- 12.9% (P < 0.001) and 23.3 +/- 24.7% (P < 0.001), respectively. Plasma levels of LDL2 (1.045 < d < 1.063)-C were significantly reduced by 22.9 +/- 18.1% (P < 0.001) overall but not in FH. Gradient PAGE showed no consistent changes in the distribution of LDL particles. Thus, plasma levels of all apo B-containing lipoprotein subfractions were reduced by simvastatin, but its effects varied among the three subgroups. Cholesterol esterification rates were suppressed by 9.3 +/- 19.7% (P < 0.01) and activities of cholesteryl ester transfer protein were reduced by 30.6 +/- 21.5% (P < 0.001). Changes in CETP activity and in plasma levels of cholesterol in lipoprotein subfractions were not correlated. Thus, the changes in distribution of lipoprotein subfractions were not due mainly to CETP suppression. |
| Effects of simvastatin on the lipid profile and attainment of low-density lipoprotein cholesterol goals when added to thiazolidinedione therapy in patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, placebo-controlled trial Lewin, A. J., M. S. Kipnes, et al. (2004), Clin Ther 26(3): 379-89. Abstract: BACKGROUND: Coronary heart disease is the major cause of mortality in individuals with diabetes mellitus (DM). Given the increasingly aggressive low-density lipoprotein cholesterol (LDL-C) goals for patients with DM set by the National Cholesterol Education Program Adult Treatment Panel III and the American Diabetes Association, many patients remain above target. Treatment with thiazolidinediones (TZDs) improves glycemic control but does not lower (and may raise) LDL-C concentrations. OBJECTIVE: This study assessed the lipid-modifying efficacy and tolerability of adding the hydroxymethylglutaryl coenzyme A-reductase inhibitor simvastatin to existing TZD therapy in patients with type 2 DM. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Patients with type 2 DM who were taking a stable dose of pioglitazone or rosiglitazone and had a glycosylated hemoglobin (HbA1c) value < or =9.0% and an LDL-C concentration > 100 mg/dL were randomized to receive simvastatin 40 mg (the recommended initial dose for patients with DM) or placebo for 24 weeks. The primary end point was the effect of treatment on LDL-C concentrations. Other lipid, lipoprotein, and safety measures were also assessed. RESULTS: Two hundred fifty-three patients (127 50.2% men, 126 49.8% women; mean age, 56 years) were randomized to treatment (123 simvastatin, 130 placebo). At the end of the study, mean LDL-C concentrations were reduced 34.)% from baseline (from 134.3 to 89.5 mg/dL) in the simvastatin group and were unchanged in the placebo group (P<0.001). Simvastatin produced significant reductions in concentrations of total cholesterol, triglycerides (TG), non-high-density lipoprotein cholesterol, and apolipoprotein (apo) B compared with placebo (all, P<0.001) and significant increases in concentrations of high-density lipoprotein cholesterol (HDL-C) (P=0.002) and apo A-I (P=0.006). In patients who had not attained target concentrations of LDL-C (<100 mg/dL), TG (<150 mg/dL), or HDL-C (>45 mg/dL) at baseline, significantly more simvastatin recipients had achieved these goals at the end of the study compared with placebo recipients (LDL-C: 67.3% vs 5.2%, respectively, P<0.001; HDL-C: 95.3% vs 83.6%, P<0.05; TG: 40.8% vs 11.0%, P<0.001). Simvastatin was well tolerated, and no clinically meaningful differences in the incidence of serious adverse events, treatment-related adverse events, or discontinuations due to adverse events were observed between groups. There were no significant between-group differences in glycemic control (HbA1c) or concentrations of fasting insulin, creatine phosphokinase, or hepatic transaminases. CONCLUSION: Simvastatin was an effective and generally well tolerated treatment for hyperlipidemia when used in combination with TZD therapy in this population of patients with type 2 DM. |
| Effects of simvastatin on the metabolism of polyunsaturated fatty acids and on glycerolipid, cholesterol, and de novo lipid synthesis in THP-1 cells Rise, P., C. Colombo, et al. (1997), J Lipid Res 38(7): 1299-307. Abstract: In the monocytic THP-1 cells, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor simvastatin (5 microM) enhances the conversion of exogenous linoleic (18:2 n-6) and eicosapentaenoic (20:5 n-3) acids to their long-chain polyunsaturated fatty acid (LC-PUFA) derivatives, and this effect is associated with changes in the desaturation steps. In addition, formation of monounsaturated fatty acids from endogenously synthesized precursors is increased. These metabolic changes lead to elevated LC-PUFA and fatty acid (FA) unsaturation in cells. The effects of simvastatin on FA metabolism are associated with increased synthesis of triglycerides from glycerol. The dose-effect relationships for the activity of simvastatin on total linoleic acid (LA) conversion and cholesterol synthesis reveal that enhancement of PUFA metabolism is already maximal at 0.5 microM simvastatin, whereas cholesterol synthesis is further inhibited by concentrations of simvastatin up to 5 microM. The effects of 5 microM simvastatin on PUFA metabolism are partially prevented by mevalonate (1 mM) and geranylgeraniol (5 microM) but not by farnesol (10 microM). These data indicate that HMG-CoA inhibitors have profound effects on PUFA metabolism, and that the pathways for cholesterol and PUFA synthesis are mutually modulated. |
| Effects of simvastatin, a cholesterol synthesis inhibitor, on phosphatidylcholine synthesis in HepG2 cells Yanagita, T., K. Yamamoto, et al. (1994), Clin Ther 16(2): 200-8. Abstract: The effects of the addition of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, to the medium on sterol synthesis and phosphatidylcholine (PC) synthesis were studied in HepG2 cells. The cells were cultured with simvastatin at concentrations of 10(-7) and 10(-6) mol/L for 6 hours, and radioactive lipid precursors were added 1 hour before harvesting. Simvastatin inhibited cholesterol synthesis from 14Cacetate in a dose-dependent manner. It also decreased the incorporation of 14Ccholine into PC by 30%; this decrease was accompanied by a decrease in phosphocholine cytidylyltransferase activity in cell homogenates. Simvastatin had no significant effects on the incorporation of 3Hglycerol into phospholipids. These data indicate that simvastatin has two different functions: inhibition of HMG-CoA reductase and depression of de novo synthesis of PC via the cytidine diphosphate-choline pathway, which, in turn, may result in a decrease in plasma lipid levels. |
| Effects of single administration of pravastatin sodium on hepatic cholesterol metabolism in rats Fujioka, T. and Y. Tsujita (1997), Eur J Pharmacol 323(2-3): 223-8. Abstract: Pravastatin sodium, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, was administered to rats at 500 mg/kg, and the changes in several parameters concerning the metabolism of cholesterol in the liver were determined over 12 h. HMG-CoA reductase activity began to be induced 6 h after pravastatin dosage and continued to increase for an additional 6 h. A significant reduction of serum and liver microsomal cholesterol was observed only at 9 h. At this time point, the protein mass and activity of cholesterol 7 alpha-hydroxylase were significantly decreased by 31% and 34%, respectively. Hepatic low density lipoprotein (LDL) receptor expression was not affected by pravastatin throughout the experimental period. These results suggest that, in rats, the compensatory mechanism to restore the cholesterol balance after depletion of liver cholesterol produced by a single administration of pravastatin might primarily depend on the induction of HMG-CoA reductase and might be facilitated by a reduction in cholesterol 7 alpha-hydroxylase, without the induction of hepatic LDL receptor. |
| Effects of single oral doses of scopoletin and aflatoxin B1 on the clotting time, serum cholesterol and phospholipid levels of chicks Obasi, S. C., O. U. Njoku, et al. (1994), Indian J Physiol Pharmacol 38(2): 89-94. Abstract: The plasma cholesterol and phospholipid levels as well as the bleeding time of chicks treated with single oral doses of scopoletin (60 micrograms/kg, body wt) and aflatoxin B1 (50 micrograms/kg, body wt) were measured at intervals for a period of one week (168 h). Both compounds generally increased the bleeding time (AFB1 0.8-28.7%, Scopoletin 0.5-38.2%), serum total and free cholesterol, and the serum phospholipid levels but decreased the levels of the serum esterified cholesterol fraction relative to control throughout the period of study. The extent of these changes elicited by the respective compounds and the variation in the differences between their respective effects varied with the measured parameters. The importance of the similarities in the effects elicited by aflatoxin B1 and Scopoletin was highlighted. |
| Effects of sirolimus on mesangial cell cholesterol homeostasis: a novel mechanism for its action against lipid-mediated injury in renal allografts Varghese, Z., R. Fernando, et al. (2005), Am J Physiol Renal Physiol 289(1): F43-8. Abstract: Lipoprotein abnormalities are present in a high proportion of renal transplant patients. It is accepted that dyslipidemia is associated with atherosclerosis and in the progression of renal disease. Lipid abnormalities may also play a significant role in the development of chronic allograft nephropathy. Sirolimus was found to have an antiatherosclerotic effect in the apolipoprotein E-knockout mice model of hyperlipidemia through its antiproliferative effects. As lipid-mediated renal injury is important in the pathogenesis of glomerulosclerosis which shares common pathogenic mechanisms with atherosclerosis, in this study we have tested the hypothesis that sirolimus prevents lipid-mediated renal injury through the modulation of cholesterol homeostasis of mesangial cells and its anti-inflammatory effects on macrophages. We demonstrated that sirolimus reduced lipid accumulation, as measured by oil red O staining in human mesangial cells (HMCs). Using real-time PCR, we screened the mRNA expression of lipoprotein receptors. Sirolimus significantly suppressed LDL and VLDL receptors and CD36 gene expression. It also increased cholesterol efflux from HMCs by increasing peroxisome proliferator-activated receptor-alpha (PPARalpha), PPARgamma, liver X receptor-alpha, and ATP binding cassette A1 (ABCA1) gene expression. Sirolimus overrode the suppression of cholesterol efflux and ABCA1 gene expression induced by the inflammatory cytokine IL-1beta. Furthermore, sirolimus significantly inhibited inflammatory cytokines IL-6 and TNF-alpha production in macrophages. These data suggest that sirolimus may prevent cellular cholesterol accumulation even in the presence of hyperlipidemia and inflammation, by regulating both cholesterol homeostasis and inflammatory responses. |
| Effects of soluble and insoluble fiber preparations isolated from oat, barley, and wheat on liver cholesterol accumulation in cholesterol-fed rats Oda, T., S. Aoe, et al. (1993), J Nutr Sci Vitaminol (Tokyo) 39(1): 73-9. Abstract: Effects of soluble and insoluble fiber preparations isolated from defatted oat, barley, and wheat on liver cholesterol accumulation were examined in cholesterol-fed rats. The soluble and insoluble fiber preparations were isolated by a modification of the procedure of Asp et al. Male Sprague-Dawley rats, aged 5 weeks, were fed a control diet containing 5% cellulose or diets containing soluble and insoluble fiber preparations for 9 days. Soluble fiber preparations from oat, barley, and wheat were added to diets corresponding to 1.9, 2.8, and 0.6% fiber, respectively. Insoluble fiber preparations from oat, barley, and wheat were added to diets corresponding to 3.1, 2.2, and 4.4% fiber, respectively. All of the soluble fiber preparations suppressed liver cholesterol accumulation, but they did not suppress the elevation of plasma cholesterol concentrations. A significant inverse relationship between the quantity of ingested soluble fiber and liver cholesterol accumulation was observed; n = 28, r = -0.943, p < 0.0001. None of the insoluble fiber preparations had any significant effect on liver and plasma cholesterol concentrations. These results indicate that the water-soluble fractions of oat, barley, and wheat are the active components that suppressed liver cholesterol accumulation, and that these effects are related to the quantity of ingested soluble fiber. |
| Effects of soluble sodium alginate on cholesterol excretion and glucose tolerance in rats Kimura, Y., K. Watanabe, et al. (1996), J Ethnopharmacol 54(1): 47-54. Abstract: We studied the effects of a natural sodium alginate (isolated from Laminaria angustata Kjellman var. longissima Miyabe, Phaeophyceae) (average molecular weight: 2700 kDa; AG-270) and three water-soluble low-molecular weight sodium alginates (average molecular weights, 10, 50 and 100 kDa; AG-1, AG 5, and AG-10, respectively) on cholesterol excretion and glucose tolerance in rats. AG-270, AG-5 and AG-10 enhanced cholesterol excretion into faeces. AG-270 and AG-10 inhibited blood glucose and insulin levels from rising 30 min after glucose administration. AG-5 inhibited the blood glucose level from rising 30 and 60 min after glucose administration, without affecting blood insulin levels. AG-1 had no effect on cholesterol excretion or glucose tolerance. These findings suggest that the effects of the natural sodium alginate and AG-5 and AG-10 on cholesterol excretion and glucose tolerance may be due to the inhibition of cholesterol and glucose absorption from the small intestine by the gelling of the free alginic acid converted in the stomach. These experimental results indicate that the low-molecular weight sodium alginates, AG-5 and AG-10, should be useful as dietary fibers for the prevention of obesity, hypercholesterolemia, and diabetes. |
| Effects of soy protein on levels of remnant-like particles cholesterol and vitamin E in healthy men Higashi, K., S. Abata, et al. (2001), J Nutr Sci Vitaminol (Tokyo) 47(4): 283-8. Abstract: We determined the effects of soy protein isolate (SPI) intake on remnant-like particles (RLP), lipolytic enzymes, lipid transfer protein, transaminases, sex hormones, iron, calcium, and vitamin E in healthy men. In the first randomized, crossover experiment, 14 men were given either 20 g per day of SPI or nothing (control) for each 4-week segment. After 3 weeks of SPI intake, TG and RLP cholesterol levels were significantly lower than the baseline by 13.4% (p<0.05) and 9.8% (p<0.05), respectively. However, no significant change was found in total and low-density lipoprotein (LDL) cholesterol levels or the activities of lipoprotein lipase, hepatic lipase, cholesteryl ester transfer protein, and lecithin cholesterol acyltransferase. Although the levels of transaminases. testosterone, iron, and calcium did not change, the vitamin E level was reduced from the baseline by 9.7%, a significant decrease (p<0.01). In the second study, we attempted to determine the effect of vitamin E supplement taken with SPI. For each 3-week segment, 12 men were given 20 g per day of SPI, either with or without 200 mg per day of vitamin E, in a randomized crossover design. The vitamin E level was reduced by 9.2%, a significant decrease (p<0.05), after SPI intake for 3 weeks, and vitamin E supplement increased vitamin E level significantly (p<0.05). These results demonstrate that SPI intake reduces remnant lipoproteins, TG, and the plasma level of vitamin E, although vitamin E supplementation compensates for the reduction of vitamin E. Therefore the supplementation of vitamin E may be required in subjects with long-term and abundant intake of soy protein. |
| Effects of soy protein on plasma cholesterol and bile acid excretion in hamsters Wright, S. M. and A. M. Salter (1998), Comp Biochem Physiol B Biochem Mol Biol 119(2): 247-54. Abstract: The effect of dietary casein and soy protein on lipoprotein metabolism was compared in the Golden Syrian hamster (Mesocricetus auratus). Total plasma cholesterol was similar in animals fed either protein, but significant differences were seen in lipoprotein profile. In animals fed soy protein, cholesterol concentrations were lower in very-low-density lipoproteins (VLDL) but higher in low-density and high-density lipoproteins, compared with those fed casein. Significant differences were also seen depending on the nutritional state of the animals. In casein-fed hamsters, total plasma triacylglycerol and chylomicron + VLDL cholesterol and triacylglycerol were significantly higher when blood was collected during feeding, compared with animals that had been fasted overnight. By contrast, no significant change was seen in animals on the soy protein diet. This suggests that either intestinally derived lipoproteins are more rapidly cleared on the soy protein diet or that soy inhibits feeding-induced VLDL secretion. Fecal bile acid excretion was higher in the soy protein group, and there was a significant correlation between soy intake and bile acid excretion. Hepatic cholesterol decreased as the amount of soy protein consumed increased, suggesting that it is this pool of cholesterol that is used to replace the excreted bile acids. No significant difference was seen in plasma insulin or glucagon between hamsters fed the two proteins. Plasma triiodothyronine concentrations were, however, significantly higher and thyroxine concentrations lower in the soy protein-fed animals. This study shows specific effects of dietary proteins on plasma lipoprotein concentrations dependent on nutritional status of the animal. |
| Effects of soya milk and Bifidobacterium-fermented soya milk on plasma and liver lipids, and faecal steroids in hamsters fed on a cholesterol-free or cholesterol-enriched diet Kikuchi-Hayakawa, H., N. Onodera, et al. (1998), Br J Nutr 79(1): 97-105. Abstract: The effects of freeze-dried soya milk (SM) and Bifidobacterium-fermented soya milk (FSM) on plasma and liver lipids, and faecal steroid excretion were estimated in hamsters fed on a cholesterol-free or cholesterol-enriched diet. Hamsters fed on the cholesterol-free diet containing 300 g FSM/kg had lower levels of plasma VLDL + LDL cholesterol than the animals fed on the control diet. SM in the diet produced a similar pattern without significant differences. In the cholesterol-enriched diet group, SM and FSM decreased the levels of plasma total cholesterol and VLDL + LDL-cholesterol. SM and FSM decreased the plasma triacylglycerol level in both the cholesterol-free and -enriched diet groups. The liver total cholesterol contents in the SM and FSM groups were lower than that in the control group, for hamsters fed on the cholesterol-free diet. The liver triacylglycerol content was not modified by SM or FSM in hamsters fed on either the cholesterol-free or -enriched diet. SM and FSM increased the total bile acid excretion and the proportion of cholesterol entering the cholic acid biosynthesis pathway in both the cholesterol-free and -enriched diet groups. SM and FSM did not affect neutral steroid excretion in the cholesterol-free or -enriched diet group. There was an inverse relationship between VLDL + LDL-cholesterol and faecal bile acid excretion in hamsters fed on the cholesterol-free (r -0.670, P < 0.01) and cholesterol-enriched (r -0.761, P < 0.001) diets respectively. These results indicated that SM had an anti-atherogenic effect, and that this effect was not diminished by prior fermentation. |
| Effects of soybean protein and very low dietary cholesterol on serum lipids, biliary lipids, and fecal sterols in humans Duane, W. C. (1999), Metabolism 48(4): 489-94. Abstract: Soy-base texturized vegetable protein (TVP; Archer Daniels Midland, Decatur, IL) has been used to decrease serum cholesterol and as a substitute for animal protein to achieve very low levels of dietary cholesterol. The effect of very low dietary cholesterol and of TVP on biliary lipids and fecal sterols is unclear. The study objective was to determine the effects of very low intake of dietary cholesterol, as well as TVP itself, on serum lipids, biliary lipids, and fecal sterols. We studied eight normal subjects living on a metabolic ward during three randomly ordered 6- to 7-week periods: (1) standard cholesterol diet (190 to 550 mg/d), (2) TVP-low-cholesterol diet (17 to 30 mg/d), and (3) TVP-standard cholesterol diet. By analysis of covariance (ANCOVA), reducing dietary cholesterol to these very low levels significantly decreased serum low-density lipoprotein (LDL) cholesterol (P=.048) but did not affect high-density lipoprotein (HDL) cholesterol or triglyceride. TVP resulted in a borderline significant reduction in LDL cholesterol (P=.058) with a highly significant reduction in HDL cholesterol (P=.004) and an increase in serum triglyceride (P=.010). During TVP ingestion, there was a highly significant increase in the output of fecal neutral sterols (P=.005) and a tendency for a higher output of fecal acidic sterols (P=.100). Fecal sterol balance was significantly more negative (indicating increased cholesterol synthesis) during TVP ingestion (P=.016). Neither TVP nor the very-low-cholesterol diet appreciably affected the gallbladder bile molar percent cholesterol or saturation index. The data are consistent with the hypothesis that to the extent TVP decreases serum LDL cholesterol (an effect of borderline significance in this study), the effect occurs via a reduction in the absorption of cholesterol and perhaps bile acid. However, the potential benefit of decreasing LDL cholesterol in this way seems to be at least partially offset by a concomitant reduction in HDL cholesterol and an increase in serum triglycerides. |
| Effects of SP500263, a novel selective estrogen receptor modulator, on bone, uterus, and serum cholesterol in the ovariectomized rat Sutherland, M. K., H. Brady, et al. (2003), Calcif Tissue Int 72(6): 710-6. Abstract: We describe here the activity of a novel selective estrogen receptor modulator, SP500263. When given to adult ovariectomized (OVX) rats for 28 days at doses of 0.3, 1, or 3 mg/kg/day, we found that SP500263 partially protected against OVX-induced loss of bone mineral content in the distal ends of femurs and in the whole bone. SP500263 also antagonized the OVX-induced increase in body weight. However, unlike 17beta-estradiol, SP500263 at efficacious doses did not prevent the OVX-induced loss in uterine wet weight. A small but significant effect on uterine wet weight was noted with raloxifene dosed at 1 mg/kg. As expected, SP500263 but not raloxifene acted as an estrogen antagonist on the uterus in adult rats when administered for 7 days at 30 mg/kg/day. Finally, SP500263 had no statistically significant effects on total serum cholesterol and serum triglycerides in OVX rats treated for 28 days. Raloxifene had no significant effects on body weight, bone mineral content, and serum cholesterol or triglycerides in the OVX-rat model. In summary, SP500263 is a new orally active SERM that acts in rats as an estrogen agonist on bone without causing uterine stimulatory effects. |
| Effects of specific inhibition of sterol biosynthesis on the uptake and utilization of low density lipoprotein cholesterol by HepG2 cells Panini, S. R., G. T. Everson, et al. (1991), J Lipid Res 32(10): 1657-65. Abstract: Treatment of HepG2 cells in lipoprotein-deficient media with 4,4,10 beta-trimethyl-trans-decal-3 beta-ol (TMD) abolished the incorporation of 3Hacetate into cholesterol with concomitant accumulation of squalene 2,3(S)-oxide and squalene 2,3(S):22(S),23-dioxide, indicating a specific inhibition of oxidosqualene cyclase. The activity of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase was affected in a biphasic manner, being inhibited by 30% at low concentrations of TMD and stimulated by 30% at concentrations that completely shut down oxidosqualene cyclase. Treatment with TMD (greater than 20 micrograms/ml) doubled the specific binding and internalization of low density lipoproteins (LDL) and also enhanced their degradation to a degree comparable to that produced by lovastatin, a well-known inhibitor of HMG-CoA reductase. The enhanced binding of LDL to HepG2 cells appeared to occur as a result of an increase in the number of binding sites with no change in their binding affinity for the lipoprotein. At concentrations that completely inhibited cholesterol biosynthesis, TMD did not affect the ability of LDL-derived cholesterol to stimulate cholesterol esterification by seven- to tenfold or to stimulate bile acid secretion to a lesser degree. However, TMD treatment inhibited overall bile acid secretion by 75-85%. The compound had no inhibitory effect on the rates of secretion of either apolipoprotein B or of cholesterol by HepG2 cells into the culture medium. These data demonstrate that a specific inhibition of the sterol branch of isoprenoid biosynthetic pathway in hepatic cells by TMD is sufficient to induce the expression of LDL receptors and that the cholesterol delivered by LDL is available for normal metabolic purposes of the cell. |
| Effects of spermine-conjugated Bowman-Birk inhibitor (spermine-BBI) on carcinogenesis and cholesterol biosynthesis in mice Kennedy, A. R., D. Kritchevsky, et al. (2003), Pharm Res 20(12): 1908-10. Abstract: PURPOSE: The goals of the studies reported here were to evaluate the effects of the soybean-derived protease inhibitor known as the Bowman-Birk inhibitor (BBI) and its spermine-conjugate (spermine-BBI) on the prevention of lung tumorigenesis and the reduction of heart disease parameters. METHODS: Both spermine-BBI and purified BBI (pBBI), at a dose of 20 mg/kg body weight, were administered as intraperitoneal injections to animals treated with the chemical carcinogen 3-methylcholanthrene (MCA) to determine their effects on chemically induced lung tumorigenesis in A/J mice. In addition, the effects of spermine-BBI and pBBI on the aortic cholesterol content and the percent ester in the mice were determined. RESULTS: The characteristics of the animals in the various treatment groups were comparable in terms of behavioral phenomena, weight gain, and lack of deaths during the experimental period. Thus, there was no detectable toxicity in spermine-BBI-treated mice. Both spermine-BBI and pBBI had a significant suppressive effect on MCA-induced lung tumors, with spermine-BBI being more effective than pBBI. Spermine-BBI was considerably more effective than pBBI at affecting heart-disease-related parameters. The amount of esterified cholesterol present in the aortas of mice treated with spermine-BBI was 9% lower than that of the controls. Both pBBI and spermine-BBI reduced total cholesterol levels in the blood, with pBBI reducing the cholesterol level by 15.5% and spermine-BBI by 33.3%. CONCLUSIONS: Spermine-BBI can prevent lung carcinogenesis without detectable toxic effects; therefore, it is concluded that lung targeting by the cationization of polypeptides can be achieved without apparent toxicity. The increase in retention of spermine-BBI compared to pBBI in liver tissue may make a difference for the heart disease parameters evaluated. Although spermine-BBI is capable of reducing the total cholesterol and ester levels in mice, pBBI did not have as great an effect on these parameters. Because the liver is the major site for the production of cholesterol, the localization of spermine-BBI in liver tissue may account for the greater effect of spermine-BBI on blood cholesterol levels. Spermine-BBI was administered to animals for only the first 2 months of the 4-month assay period before animal sacrifice, so the results suggest that the effects of spermine-BBI on the parameters related to heart disease are long-lasting, as are the effects of both pBBI and spermine-BBI on lung tumorigenesis. |
| Effects of sphingomyelin and cholesterol on lipoprotein lipase-mediated lipolysis in lipid emulsions Arimoto, I., H. Saito, et al. (1998), J Lipid Res 39(1): 143-51. Abstract: Lipoprotein lipase (LPL) hydrolyzes triacylglycerol (TG) of TG-rich lipoproteins. We investigated the effects of sphingomyelin (SM) and cholesterol (Chol) on the lipolysis of lipid emulsions by LPL using human apolipoprotein C-II (apoC-II) or plasma as an activator. Kinetic studies of the lipolysis rates clearly demonstrated that the primary effect of the activator on the LPL reaction was not to increase the affinity of LPL for the emulsion surface, but to enhance LPL catalytic activity. Incorporation of SM into the emulsion surface caused increases in Km(app) and decreases in Vmax(app), indicating that SM inhibited lipolysis by decreasing both affinity for substrates and catalytic activity of LPL. SM was also found to affect possible factors related to the lipolysis rates; that is, SM increased TG solubility in surface layers and decreased apoC-II binding to the emulsion surface. Interestingly, Chol did not affect the lipolysis rates even though it decreased TG solubility and apoC-II binding. These results indicated that neither TG solubility nor amount of apoC-II binding were determinate factors in LPL-mediated lipolysis under physiological conditions. Our results suggest that the content of SM in the lipoprotein surface plays an important role by controlling lipoprotein lipase-mediated lipolysis, and that cholesterol enrichment in the lipoprotein surface has no influence on lipolysis, but may affect other metabolic processes such as uptake by the liver through the selectivity of apolipoprotein binding. |