Lower Plasma Total Cholesterol Research Articles

A Spread Enriched with Plant Sterol-Esters Lowers Blood Cholesterol and Lipoproteins without Affecting Vitamins A and E in Normal and Hypercholesterolemic Japanese Men and Women

The objective of the study was to investigate whether different initial baseline cholesterol levels modulate the efficacy of a spread enriched with plant sterol-esters (PS) in lowering blood cholesterol in a Japanese population consuming their usual diet. Healthy adults with a mean age of 45 y and mean plasma total cholesterol (TC) level of 6.5 mmol/L were recruited to participate in a double-blind trial comprised of a run-in period of 1 wk, followed by two intervention periods of 3 wks in a 2 x 2 crossover design and a post-trial follow-up of 3 wk. Volunteers consumed two spreads, one enriched with PS (12 g/100 g plant sterols) and a control spread not fortified with PS. Recommended spread intake was 15 g/d. Effects on plasma lipids, lipoproteins, beta-carotene and vitamins A and E were assessed. Plasma TC and LDL cholesterol (LDL-C) concentrations were 5.8 and 9.1% lower, respectively, when subjects consumed the PS spread than when they consumed the control spread (P < 0.001). Subjects were divided into two groups [normal and mildly cholesterolemic (TC <5.7 mmol/L) and hypercholesterolemic (TC >/= 5.7 mmol/L)]. Reductions (P < 0.001) in TC and LDL-C due to treatment in the former group were 4.9 and 7.9%, respectively. In the hypercholesterolemic group, the reductions (P < 0.001) were 7.1 and 10.6%, respectively. The decreases did not differ between normal/mildly cholesterolemic and hypercholesterolemic subjects. Plasma apolipoprotein B (apoB) and remnant-like particle (RLP) cholesterol (RLP-C) concentrations were lower when subjects consumed the PS spread (44.3 g/L) than the control spread (49.7 g/L). Plasma beta-carotene concentration was lower (P < 0.001) in subjects consuming the PS spread than in the control. Changes in plasma vitamins A and E levels did not differ after intake of the PS and control spreads. In conclusion, consumption of a PS-enriched spread effectively lowered plasma TC, LDL-C, apoB and RLP-C regardless of baseline plasma TC at an intake of 1.8 g/d of plant sterols.

Whole fat rice bran reduces the development of early aortic atherosclerosis in hypercholesterolemic hamsters compared with wheat bran

In this study, Golden Syrian hamsters were fed a nonpurified hypercholesterolemic diet containing 10% coconut oil, 0.05% cholesterol and 20% wheat bran for 2 weeks (HCD) and based on mean plasma cholesterol levels were divided into four groups of 15. Hamsters were then fed the HCD or the HCD containing either 20% de-fatted rice bran (rice fiber), 20% heat-stabilized whole fat rice bran (WFRB), or 20% oat bran in place of wheat bran for 10 weeks. The rice fiber, WFRB, and oat bran diets significantly lowered plasma total cholesterol and very low- and low-density lipoprotein cholesterol levels compared to the wheat bran diet with no reductions in high-density lipoprotein cholesterol. Also, the WFRB diet significantly lowered plasma nonHDL-C levels compared to the rice fiber and oat bran diets. Aortic fatty streak formation was significantly reduced by WFRB diet compared to the wheat bran and rice fiber diets but not the oat bran. This study shows that whole fat rice bran reduces plasma cholesterol levels and the development of early aortic atherosclerosis in hypercholesterolemic hamsters similar to oat bran.

The Hypocholesterolemic Effect of High Amylose Cornstarch in Rats Is Mediated by an Enlarged Bile Acid Pool and Increased Fecal Bile Acid Excretion, Not by Cecal Fermented Products

Sham-operated and cecectomized rats were fed for 21 d a cholesterol-free purified diet containing (200 g/kg) either normal cornstarch (CS) or high amylose cornstarch (HACS). In both types of rats, those fed the HACS diet had a significantly lower plasma total cholesterol concentration and a significantly larger intestinal bile acid pool than those fed the CS diet. In cecectomized rats, those fed the HACS diet had significantly lower plasma HDL and LDL cholesterol concentrations, a significantly greater fecal bile acid excretion and a significantly lower hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase mRNA concentration than those fed the CS diet. The plasma triglyceride concentration and LDL-receptor mRNA concentration were not affected by the diet or cecectomy. In sham-operated rats, the propionate concentration in the cecal contents was significantly greater in those fed the HACS diet than in those fed the CS diet. Compared with sham-operated rats, cecectomized rats had significantly enhanced cholesterol 7alpha-hydroxylase activity. In intact rats, biliary bile acid flux into the small intestine was significantly greater in those fed the HACS diet than in those fed the CS diet. Thus, the hypocholesterolemic effect of HACS appears to be mediated by accelerated fecal excretion of bile acids and increases in the intestinal pool and biliary flux of bile acids, and not by cecal fermentation products.

A single daily dose of soybean phytosterols in ground beef decreases serum total cholesterol and LDL cholesterol in young, mildly hypercholesterolemic men , , ,

Consumption of phytosterol-supplemented margarine lowers total plasma cholesterol (TC) and LDL-cholesterol concentrations in older middle-aged hypercholesterolemic individuals. The effects of incorporating phytosterols into lower-fat foods on the plasma lipids of young men at increased risk of developing cardiovascular disease have not been studied. We tested the hypothesis that a single daily dose of soybean phytosterols added to ground beef will lower plasma TC and LDL-cholesterol concentrations in mildly hypercholesterolemic young men. In a triple-blind, 4-wk study, 34 male college students with elevated plasma TC (5.85 +/- 0.70 mmol/L), LDL cholesterol (4.02 +/- 0.60 mmol/L), and TC:HDL cholesterol (5.5 +/- 1.2) were randomly assigned to the control (ground beef alone) or treatment (ground beef with 2.7 g of phytosterols) group. The phytosterol mixture was two-thirds esterified and one-third nonesterified and consisted of beta-sitosterol (48%), campesterol (27%), and stigmasterol (21%). Consumption of phytosterol-supplemented ground beef lowered plasma TC and LDL-cholesterol concentrations and TC:HDL cholesterol from baseline by 9.3%, 14.6%, and 9.1%, respectively (P < 0.001). The LDL particle size did not change, suggesting that the decrease was primarily of particle number. The decreases were similar in subjects with (n = 8) and without (n = 9) a family history of premature cardiovascular disease. No significant changes were found in the control group. Phytosterol-supplemented ground beef effectively lowers plasma TC and LDL cholesterol and has the potential to become a functional food to help reduce the risk of cardiovascular disease.

Trans Fatty Acids Affect Lipoprotein Metabolism in Rats

This study was designed to investigate the effects of oleic (CIS), palmitic (SAT) and trans fatty acids (TRANS) on cholesterol metabolism. Rats fed the TRANS diet had lower plasma total cholesterol (P < 0.005) and non-HDL-cholesterol (non HDL-C) concentrations (P < 0.005) compared with their CIS-fed counterparts. Plasma HDL-C was highest in rats fed the SAT diet (P = 0.01). An in vivo assay of reverse cholesterol transport (RCT) was performed whereby radiolabeled cholesterol was delivered to the liver as acetylated LDL and the reappearance of label into plasma and HDL was determined. Plasma radioactivity in TRANS-fed rats was lower than in their SAT-fed counterparts (P = 0.01), and consistent with the cholesterol distribution in plasma, the difference was due to lower [(3)H]-cholesterol in lower density lipoproteins. Despite diet-induced differences in the cholesterol and phospholipid concentrations and fatty acid composition of HDL, the amount of label in HDL did not differ among groups, suggesting that consumption of these diets resulted in HDL populations with similar capacity to participate in RCT. The present findings suggest that dietary trans fatty acids regulate the metabolism of apolipoprotein B-containing lipoproteins in rats and that the effect may be masked in species possessing high plasma cholesteryl ester transfer protein (CETP) activity. These results reinforce the important role of CETP activity in determining the distribution of plasma cholesterol in response to dietary trans fatty acids.

Oral Chromium Picolinate Improves Carbohydrate and Lipid Metabolism and Enhances Skeletal Muscle Glut-4 Translocation in Obese, Hyperinsulinemic (JCR-LA Corpulent) Rats

Human studies suggest that chromium picolinate (CrPic) decreases insulin levels and improves glucose disposal in obese and type 2 diabetic populations. To evaluate whether CrPic may aid in treatment of the insulin resistance syndrome, we assessed its effects in JCR:LA-corpulent rats, a model of this syndrome. Male lean and obese hyperinsulinemic rats were randomly assigned to receive oral CrPic [80 microg/(kg. d); n = 5 or 6, respectively) in water or to control conditions (water, n = 5). After 3 mo, a 120-min intraperitoneal glucose tolerance test (IPGTT) and a 30-min insulin tolerance test were performed. Obese rats administered CrPic had significantly lower fasting insulin levels (1848 +/- 102 vs. 2688 +/- 234 pmol/L; P < 0.001; mean +/- SEM) and significantly improved glucose disappearance (P < 0.001) compared with obese controls. Glucose and insulin areas under the curve for IPGTT were significantly less for obese CrPic-treated rats than in obese controls (P < 0.001). Obese CrPic-treated rats had lower plasma total cholesterol (3.57 +/- 0.28 vs. 4.11 +/- 0.47 mmol/L, P < 0.05) and higher HDL cholesterol levels (1.92 +/- 0.09 vs. 1.37 +/- 0.36 mmol/L, P < 0.01) than obese controls. CrPic did not alter plasma glucose or cholesterol levels in lean rats. Total skeletal muscle glucose transporter (Glut)-4 did not differ among groups; however, CrPic significantly enhanced membrane-associated Glut-4 in obese rats after insulin stimulation. Thus, CrPic supplementation enhances insulin sensitivity and glucose disappearance, and improves lipids in male obese hyperinsulinemic JCR:LA-corpulent rats.

Antioxidative functions of natto, a kind of fermented soybeans: effect on LDL oxidation and lipid metabolism in cholesterol-fed rats.

Natto water-soluble fractions, low-molecular-weight viscous substance, and soybean water extract, which had an inhibitory effect on the oxidation of low-density lipoproteins (LDL) in vitro, were fed to rats for 3 weeks. These fractions had no influence on the growth of rats, which were fed a basal diet containing 1% cholesterol, but lowered plasma triglyceride and total cholesterol. Inhibition of copper-oxidation of plasma and LDL ex vivo, and a reduction in lipid peroxidation in liver and aorta in vivo, were also observed. The antioxidant enzymes were not induced in rats fed natto fraction diets. These results demonstrate that ingestion of the natto fractions led to inhibition of LDL oxidation, and that the fractions perform direct antioxidant action in the body. It is suggested that natto fractions might help to prevent arteriosclerosis, as they appear to reduce lipid peroxidation and improve lipid metabolism.

The biomimetic [Cr(3)O(O(2)CCH(2)CH(3))(6)(H(2)O)(3)](+ )decreases plasma insulin, cholesterol, and triglycerides in healthy and type II diabetic rats but not type I diabetic rats.

The in vivo effects of administration of the synthetic, functional biomimetic cation [Cr(3)O(O(2)CCH(2)CH(3))(6)(H(2)O)(3)](+) to healthy and type I and type II diabetic model rats are described. In contrast to current chromium-containing nutrition supplements, which only serve as sources of absorbable chromium, the trinuclear cation has been shown in in vitro assays to interact with the insulin receptor, activating its kinase activity, presumably by trapping the receptor in its active conformation. Thus, treatment of rats with the trinuclear cation would be expected to result in changes in lipid and carbohydrate metabolism related to insulin action. After 24 weeks of intravenous administration (0-20 micro g Cr/kg body mass), the cation results in a concentration-dependent lowering of levels of fasting blood plasma LDL cholesterol, total cholesterol, triglycerides, and insulin and of 2-h plasma insulin and glucose levels after a glucose challenge; these results confirm a previous 12-week study examining the effect of the synthetic cation on healthy rats and are in stark contrast to those of administration of other forms of Cr(III) to rats, which have no effect on these parameters. The cation has little, if any, effect on rats with STZ-induced diabetes (a type I diabetes model). However, Zucker obese rats (a model of the early stages of type II diabetes) after 24 weeks of supplementation (20 micro g/kg) have lower fasting plasma total, HDL, and LDL cholesterol, triglycerides, and insulin levels and lower 2-h plasma insulin levels. The lowering of plasma insulin concentrations with little effect on glucose concentrations suggests that the supplement increases insulin sensitivity.

Effect of esterified 4-desmethylsterols and -stanols or 4,4'-dimethylsterols on cholesterol and bile acid metabolism in hamsters.

4-Desmethylsterols and -stanols reduce plasma total cholesterol (TC) and LDL cholesterol by inhibition of intestinal cholesterol absorption, while the cholesterol-lowering potential of 4,4'-dimethylsterols is less well defined. The present study aimed to compare the effects of 4-desmethylsterols, -stanols, and 4,4'-dimethylsterols on plasma and hepatic cholesterol, sterol excretion and bile acid metabolism. Male golden Syrian hamsters were fed diets containing 13 g/100 g fat, 008 g/100 g cholesterol and 0 (control), 0.24 or 0.48% (w/w) esterified 4-desmethylsterols (sterols) and esterified hydrogenated 4-desmethylsterols (stanols) from common vegetable oils or esterified 4,4'-dimethylsterols from rice bran oil for 5 weeks. Sterol and stanol esters at the dose of 0.24% were equally effective and significantly (P<0.05) lowered TC by 15%, while 0.24% 4,4-dimethylsterols reduced TC by 10%. Liver total and esterified cholesterol concentrations were significantly (P<0.05) lowered by 40, 22, 43 and 31% in hamsters fed 0.48% sterols, 0.24% stanols, 0.48% stanols or 0.48% dimethylsterols, respectively. Daily faecal bile acid excretion and hepatic cholesterol 7alpha-hydroxylase activity were not altered, indicating that sterols, stanols and dimethylsterols had no effect on the intestinal re-absorption of bile acids or on hepatic bile acid synthesis. Daily excretion of cholesterol was significantly higher in hamsters fed esterified sterols and stanols, but was only slightly increased in those fed dimethylsterols. The results indicate that esterified sterols and stanols were equally effective in lowering plasma TC and LDL cholesterol, while dimethylsterol esters caused a weaker cholesterol-lowering effect. Sterols and stanols achieve their cholesterol-lowering effect by stimulating faecal cholesterol excretion through inhibiting intestinal cholesterol absorption, but do not affect bile acid excretion. Other mechanisms need to be considered to explain the effect on plasma and hepatic cholesterol of dimethylsterols.

Effect of esterified 4-desmethylsterols and -stanols or 4,4′-dimethylsterols on cholesterol and bile acid metabolism in hamsters

4-Desmethylsterols and -stanols reduce plasma total cholesterol (TC) and LDL cholesterol by inhibition of intestinal cholesterol absorption, while the cholesterol-lowering potential of 4,4′-dimethylsterols is less well defined. The present study aimed to compare the effects of 4-desmethylsterols, -stanols, and 4,4′-dimethylsterols on plasma and hepatic cholesterol, sterol excretion and bile acid metabolism. Male golden Syrian hamsters were fed diets containing 13 g/100 g fat, 0·08 g/100 g cholesterol and 0 (control), 0·24 or 0·48 % (w/w) esterified 4-desmethylsterols (sterols) and esterified hydrogenated 4-desmethylsterols (stanols) from common vegetable oils or esterified 4,4′-dimethylsterols from rice bran oil for 5 weeks. Sterol and stanol esters at the dose of 0·24 % were equally effective and significantly (P&lt;0·05) lowered TC by 15 %, while 0·24 % 4,4-dimethylsterols reduced TC by 10 %. Liver total and esterified cholesterol concentrations were significantly (P&lt;0·05) lowered by 40, 22, 43 and 31 % in hamsters fed 0·48 % sterols, 0·24 % stanols, 0·48 % stanols or 0·48 % dimethylsterols, respectively. Daily faecal bile acid excretion and hepatic cholesterol 7α-hydroxylase activity were not altered, indicating that sterols, stanols and dimethylsterols had no effect on the intestinal re-absorption of bile acids or on hepatic bile acid synthesis. Daily excretion of cholesterol was significantly higher in hamsters fed esterified sterols and stanols, but was only slightly increased in those fed dimethylsterols. The results indicate that esterified sterols and stanols were equally effective in lowering plasma TC and LDL cholesterol, while dimethylsterol esters caused a weaker cholesterol-lowering effect. Sterols and stanols achieve their cholesterol-lowering effect by stimulating faecal cholesterol excretion through inhibiting intestinal cholesterol absorption, but do not affect bile acid excretion. Other mechanisms need to be considered to explain the effect on plasma and hepatic cholesterol of dimethylsterols.

Plasma Lipoprotein Cholesterol in Rats Fed a Diet Enriched in Chitosan and Cholesterol.

To investigate the effect of dietary chitosan on plasma lipoprotein cholesterol metabolism, male Sprague-Dawley (SD) rats fed a cholesterol-enriched diet containing cellulose (CE) or chitosan (CS) were studied for 2 wk. Lower plasma total cholesterol, low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol were observed in rats fed a diet containing chitosan. In addition, significantly higher high-density lipoprotein (HDL) cholesterol and HDL2 cholesterol were observed in rats after 2 wk of chitosan feeding. Rats fed the chitosan diet had increased triacylglycerol percentages and decreased free cholesterol, cholesteryl ester and phospholipid percentages in VLDL lipid composition. Chitosan significantly decreased the surface lipid proportions and increased the core lipid proportions in VLDL particles. In addition, the ratios of surface lipids to core lipids of the VLDL particles in rats fed a diet containing chitosan were significantly decreased. A significantly lower plasma apolipoprotein B (Apo B) concentration was observed in rats fed the chitosan diet as compared to those fed the cellulose diet. No significant difference in plasma triacylglycerols or glucose levels was observed between the two dietary groups. Results from this study suggest that chitosan may alter the VLDL particle size and also play an important role in the regulation of lipoprotein metabolism in rats.

Cereal grains and coronary heart disease.

Cereal grains and their products provide around 30% of total energy intake in British adults, (much more than any of the other major food groups). Coronary heart disease (CHD) is the largest single cause of death in Britain and many other Western countries. This review examines the question whether there is a relation between cereal consumption and CHD. Several of the nutrients in cereals have known potential for reducing risk factors for CHD: the linoleic acid, fibre, vitamin E, selenium and folate. Cereals also contain phytoestrogens of the lignan family and several phenolic acids with antioxidant properties. Processing generally reduces the content of these nutrients and bioprotective substances. Although cereals at the farm gate are very low in salt, processed cereal foods, eg bread and some breakfast cereals, are high-salt foods and thus could contribute to raising blood pressure. Human experiments have clearly shown that oat fibre tends to lower plasma total and LDL cholesterol but wheat fibre does not. Rice bran and barley may also lower cholesterol but most people do not eat enough barley to have an effect. Cereal foods with low glycaemic index such as pasta and oats are beneficial for people with diabetes and might lower plasma lipids. Between 1996 and 2001 an accumulation of five very large cohort studies in the USA, Finland and Norway have all reported that subjects consuming relatively large amounts of whole grain cereals have significantly lower rates of CHD. This confirms an earlier report from a small British cohort. The protective effect does not seem to be due to cholesterol-lowering. While cohort studies have shown this consistent protective effect of whole grain cereals, there has been (only one) randomised controlled secondary prevention trial of advice to eat more cereal fibre. In this there was no reduction of the rate of reinfarction. The trial had some weaknesses, eg there were eight different diets, compliance was not checked objectively, and duration was for only 2 y. It appears valid to make health claims (as now permitted by the US FDA) that whole grain cereal foods and oat meal or bran may reduce the risk of CHD.

Variants of the microsomal triglyceride transfer protein gene are associated with plasma cholesterol levels and body mass index

The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins from liver and intestine. We set out to study the phenotypic modulation of all common genetic variants in the MTP gene. In addition, we aimed at characterizing the association between the various polymorphisms. A total of 564 healthy men were genotyped for the MTP -493 G/T, -400 A/T, and -164 T/C promoter polymorphisms, as well as the Q/H 95, I/T 128, Q/E 244, and H/Q 297 missense polymorphisms. The -493 G/T, -164 T/C, and I/T 128 polymorphisms showed to be in almost complete linkage disequilibrium. Subjects homozygous for the less common -493 T, -164 C, and T 128 alleles showed significantly lower plasma total and LDL cholesterol levels and plasma LDL apoB levels, and also significantly higher body mass index (BMI) and plasma insulin levels compared with carriers of the common alleles. The associations between plasma total cholesterol and MTP -493 genotype was verified in a cohort consisting of 1,117 disease-free control subjects of the West of Scotland Coronary Prevention Study (WOSCOPS). None of the other polymorphisms showed any significant change in either lipid and lipoprotein levels or anthropometric variables. In summary, two promoter polymorphisms and one missense polymorphism in the MTP gene alter plasma total and LDL cholesterol levels, plasma LDL apoB levels, BMI, and insulin levels. This may, in turn, have implications for genetic regulation of cardiovascular risk factors.

Gender and hormonal status affect the regulation of hepatic cholesterol 7α-hydroxylase activity and mRNA abundance by dietary soluble fiber in the guinea pig

Dietary soluble fiber (SF) consistently lowers plasma LDL cholesterol (LDL-C) concentrations, however, secondary mechanisms governing this reduction are not completely defined. Moreover, these mechanisms appear to differ with gender. Male, female and ovariectomized (to mimic menopause) guinea pigs were used to assess effects of gender, hormonal status and SF on activity and expression of hepatic cholesterol 7α-hydroxylase (CYP7). Diets were identical except for fiber source (control 10% cellulose, SF 5% psyllium/5% pectin). SF intake resulted in 44% lower plasma total cholesterol, 51% lower plasma LDL-C and 22% lower plasma triacylglycerol (TAG) concentrations. However, ovariectomized guinea pigs fed either the control or SF diets, had the highest plasma LDL-C and TAG levels ( P<0.01). SF altered hepatic cholesterol metabolism by effectively reducing hepatic free cholesterol, TAG and microsomal free cholesterol, while activity of CYP7, the rate-limiting enzyme of cholesterol catabolism, was up-regulated. Hepatic CYP7 mRNA abundance paralleled the increase in enzyme activity. Ovariectomized guinea pigs had lowest activity and expression of hepatic CYP7 even after intervention with SF. These results suggest that induction of hepatic CYP7 activity may account, in large part, for the hypocholesterolemic effect of SF. Gender and hormonal status influence metabolic responses to dietary SF with estrogen deprivation leading to the most detrimental lipid profile.

F 12511, a novel ACAT inhibitor, and atorvastatin regulate endogenous hypercholesterolemia in a synergistic manner in New Zealand rabbits fed a casein-enriched diet

F 12511, a novel ACAT inhibitor, lowers plasma cholesterol levels in New Zealand rabbits fed a cholesterol-free casein-rich diet. In rabbits endogenous hypercholesterolemia pre-established for 8 weeks was used to compare treatments with F 12511 and atorvastatin for a further 8-week period, and to determine whether both agents act synergistically. F 12511 appears to be 3–4-fold more potent than atorvastatin in reducing total plasma cholesterol (active doses ranging from 0.16 to 2.5 and from 1.25 to 10 mg/kg per day, respectively) while the hypocholesterolemic efficacy of both compounds at 2.5 mg/kg per day amounted to 70 and 45%, respectively. A reduction by as much as 75% of esterified cholesterol in liver mediated by F 12511 could account for the decrease of plasma VLDL, LDL and apo B-100, whereas a reduction of the LDL production rate has been described as the main mechanism underlying the atorvastatin effect. F 12511 modified adrenal cholesterol balance only at the largest dose studied. In a further experiment the co-administration of threshold doses of F 12511 and atorvastatin (0.63 and 1.25 mg/kg per day, respectively) lowered plasma total cholesterol and apo B-100 containing lipoproteins to a greater extent and more rapidly than either agent alone. In the liver a decrease by atorvastatin in free cholesterol substrate for ACAT may amplify the effect of F 12511 on cholesteryl ester content leading to a diminution, in at least an additive manner, of the assembly and secretion of atherogenic lipoproteins in New Zealand rabbits which have developed an endogenous hypercholesterolemia. Thus, the combination of the ACAT inhibitor F 12511 with atorvastatin can represent a better approach than either agent alone to regulate lipoprotein metabolism in certain pathophysiological situations.

Effect of ER-27856, a novel squalene synthase inhibitor, on plasma cholesterol in rhesus monkeys: comparison with 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors

Squalene synthase (SQS; EC 2.5.1.21) plays an important role in the cholesterol biosynthetic pathway. We discovered ER-28448, 5-{N-[2-butenyl-3-(2-methoxyphenyl)]-N-methylamino}-1,1-penthylidenebis(phosphonic acid) trisodium salt, as a potent and selective inhibitor of SQS. ER-28448 inhibited SQS in rat liver microsome with an IC50 value of 3.6 nm. We also prepared ER-27856, the tripivaloyloxymethyl ester prodrug of ER-28448. Although less active than ER-28448 in a liver microsome assay, ER-27856 more potently inhibited cholesterol biosynthesis in rat hepatocytes; and ER-27856 orally inhibited de novo cholesterol biosynthesis in Sprague-Dawley rats, with an ED50 value of 1.6 mg/kg. In HepG2 cells, ER-27856 upregulated low density lipoprotein receptor activity to 2.1 times that of control. A time-course study indicated that the inhibitory effect of ER-27856 on cholesterol biosynthesis in rats continued for up to 8 h. In a study of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMGRIs), atorvastatin actively suppressed cholesterol biosynthesis for 8 h, whereas the effect of pravastatin and simvastatin diminished at 4 and 8 h, respectively. In rhesus monkeys, 4 days of oral administration of ER-27856 lowered plasma total cholesterol (TCHO) more potently than did these HMGRIs. Whereas atorvastatin significantly elevated plasma alanine aminotransferase, a marker of hepatotoxicity, to 3.7 times at 100 mg/kg, ER-27856 increased the level only 1.4 times at 10 mg/kg, at which doses the hypocholesterolemic effect was equivalent. During 28 days of administration, ER-27856 reduced TCHO and non-high density lipoprotein (non-HDL) cholesterol by 72 and 95%, respectively.These results demonstrate that ER-27856 had more potent hypocholesterolemic activity and less hepatotoxic effect than HMGRIs. ER-27856 may contribute to the treatment of hypercholesterolemic patients.

Consumption of ground bison does not increase early atherosclerosis development in hypercholesterolemic hamsters

The present study investigated the effect of substituting the source of dietary protein in a hypercholesterolemic animal model. Sixty male Golden Syrian hamsters approximately 10 weeks of age were placed on a chow diet for one week. The hamsters were then divided into one of four groups, 15 hamsters per group, based on similar mean plasma cholesterol concentrations and fed a semipurified, hypercholesterolemic diet containing 20% by weight of either soy protein, casein, lyophilized ground bison, or lyophilized ground beef and 0.05% cholesterol for 8 weeks. After 8 weeks of dietary treatment, the soy protein group had significantly lower plasma total cholesterol (TC), nonHDL-C (very low- and low-density lipoprotein cholesterol), and HDL-C (high-density lipoprotein cholesterol) concentrations compared to the casein (−20, −23, and −18%; respectively), bison (−24, −32, and −19%; respectively), and beef (−34, −41, and −30%; respectively). The bison and casein groups had significantly lower plasma TC (−14 and −18%, respectively), nonHDL-C (−14% and −23%, respectively), and HDL-C (−14 and −15%, respectively) concentrations compared to the beef. The soy protein, bison, and casein groups had significantly lower plasma triglycerides (TG) concentrations compared to the beef (−49, −25, and −37%; respectively). Unexpectedly the bison and beef groups had significantly reduced early atherosclerosis compared to the soy protein (−50 and −43%, respectively) and casein (−68 and −64%, respectively). The soy protein group also had significantly reduced early atherosclerosis compared to the casein (−37%). In conclusion, plasma nonHDL-C may not be a good indicator of the development of early atherosclerosis in the hamster model and that the reduced early aortic atherosclerosis in the bison fed hamsters may be due in part to both the lipid and protein composition of the bison.

Effect of dietary chitosans with different viscosity on plasma lipids and lipid peroxidation in rats fed on a diet enriched with cholesterol.

To investigate the effect of dietary chitosan on lipid metabolism, male SD (Sprague-Dawley) rats were fed a cholesterol-enriched diet containing 5% cellulose (CE), 5% chitosan (CCS; high viscosity), or 5% chitosan (FCS; low viscosity) for 4 weeks. The two types of chitosan with a comparable degree of deacetylation had a different molecular weight and intrinsic viscosity. Significantly (p < 0.05) lower plasma total cholesterol, LDL-cholesterol and VLDL-cholesterol concentrations were observed in the rats fed on the chitosan diets. In addition, chitosan significantly increased the fecal cholesterol and triglyceride contents. Although no significant difference in body weight was found among the dietary groups, the rats fed on the chitosan diets had lower relative liver weight when compared with those fed on the cellulose diet. Both of the chitosan groups had significantly lower liver total lipid and total cholesterol contents compared to the cellulose group, although the FCS group was less effective. The plasma and liver thiobarbituric acid reactive substances (TBAR) values were similar in the CE and FCS groups, while the CCS group had increased liver TBAR values. Although a significant increase in liver glucose-6-phosphate dehydrogenase activity was observed in the CCS group, no significant change was found in the FCS group. The observed influence of chitosans with different viscosity on the plasma lipid level, liver lipids and lipid peroxidation suggests that, while the hypocholesterolemic action of chitosans with different viscosity was similar, changes in the liver lipids and liver peroxidation status depended on their molecular weight when the deacetylation degree was comparable.

An Isomeric Mixture of Conjugated Linoleic Acids But Not Pure cis-9,trans-11-Octadecadienoic Acid Affects Body Weight Gain and Plasma Lipids in Hamsters

We report the effect of an atherogenic diet supplemented with cis-9, trans-11-octadecadienoic acid (c9t11), linoleic acid (LA) or an isomeric mixture of conjugated linoleic acids (CLA) on plasma lipids, weight gain and food intake of male Golden Syrian hamsters. Animals were assigned to three diet groups (n = 10), and fed nonpurified diet, supplemented with 10% hydrogenated coconut oil and 0.05% cholesterol for 6 wk. The first diet group was further supplemented with 1% CLA (CLA group), the second diet group with 0.2% c9t11 (c9t11 group) and the third group with 0.2% LA (LA group). The diets were designed to have equivalent levels of c9t11 in the CLA and c9t11 groups. At 2 and 6 wk of feeding, the CLA group had significantly lower plasma triglyceride and total cholesterol concentrations than either the c9t11 or the LA groups. HDL-cholesterol did not differ among diet groups. The CLA group had significantly lower weight gain but greater food intake than either the c9t11 or the LA groups. There were no significant differences between the c9t11 and the LA groups in any of the variables measured. We conclude that under our experimental conditions of short-term feeding, c9t11, thought to be the active compound in CLA, does not produce the same effect as the isomer mixture.

Hypolipidemic effect of NK-104, a potent HMG-CoA reductase inhibitor, in guinea pigs

The hypolipidemic effect of NK-104 and its mechanisms of action (effects on hepatic sterol synthesis, low density lipoprotein (LDL)-receptor expression and very low density lipoprotein (VLDL) secretion) were studied in guinea pigs using simvastatin as a reference substance. There was a dose-dependent and significant reduction of both plasma total cholesterol (17.4, 24.5 and 45.3% at 0.3, 1 and 3 mg/kg, respectively) and triglycerides (21.1 and 32.2% at 1 and 3 mg/kg, respectively) after 14-day administration of NK-104. Simvastatin at 30 mg/kg lowered plasma total cholesterol (25.0%) but not triglyceride levels. NK-104 (3 mg/kg) and simvastatin (30 mg/kg) inhibited hepatic sterol synthesis by approximately 80%, 3 h after dosing, and enhanced LDL receptor binding-capacity of liver membranes 1.5-fold after 14-day dosing. The former group accelerated LDL clearance somewhat more markedly than the latter, and increased fractional catabolic rate 1.8-fold (vs. 1.4-fold). Furthermore, only the NK-104 (3 mg/kg) suppressed VLDL secretion into the liver perfusate (triglyceride, 19.9%; apoB, 24.2%) with extensive reduction of hepatic sterol synthesis caused by prolonged action. These results indicate that NK-104 and simvastatin at 10 times the dosage of the former, similarly enhances hepatic LDL receptor; however, only NK-104 with prolonged action suppresses VLDL secretion to show higher cholesterol-lowering potency and triglyceride-reducing effect.