Effects of MK-733 (simvastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on intestinal acylcoenzyme A:cholesterol acyltransferase activity in rabbits

MK-733 (simvastatin), a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, was found to inhibit the absorption of cholesterol from the gastrointestinal tract in cholesterol-fed rabbits (Ishida et al. (1988) Biochim. Biophys. Acta 963, 35-41). To clarify the mechanism of action, the effects of MK-733 on acyl coenzyme A:cholesterol acyltransferase (ACAT) and cholesterol esterase activities, which are thought to participate in the absorption of cholesterol, were examined. Dietary administration (0.03% in a 1% cholesterol diet for 7 days, approx. 10 mg/kg) of MK-733 to cholesterol-fed rabbits was found to inhibit the increase in serum total cholesterol levels, and caused a 70% reduction in ACAT activity in microsomes of intestinal mucosa relative to those observed in concurrent control rabbits. MK-733 did not affect cholesterol esterase activity in the cytosol of the intestinal mucosa. The inhibitory effect of MK-733 on cholesterol absorption in cholesterol-fed rabbits is though to be related to a reduction in microsomal ACAT activity in the intestinal mucosa.     

Effect of CS-514, a competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase, on cholesterol gallstone formation in hamsters

Male golden hamsters fed a glucose diet as a model for cholesterol gallstone formation were used to investigate the effect of CS-514 on the lithogenicity of bile. Treatment with 0.05% (w/w) CS-514 in the diet for 1-4 weeks caused a decrease in plasma cholesterol and triacylglycerol levels. A marked increase in hepatic hydroxymethylglutaryl-CoA reductase activity in vitro and also an increased de novo cholesterol synthesis in the liver were induced by treatment with CS-514 for 1-4 weeks. The concentration of free cholesterol in liver microsomes and the cholesterol 7 alpha-hydroxylase activity were both decreased by treatment with CS-514 for 1 week, but were not affected by treatment for 4 weeks. The cholesterol output into bile and the lithogenic index of bile were double those of the control (glucose diet only) following treatment with CS-514 for 4 weeks, and the subsequent incidence of cholesterol gallstone formation was elevated. The content of free cholesterol and cholesterol ester in the liver was not affected by treatment with CS-514 for 4 weeks. These results suggest that long-term treatment with CS-514 causes a compensatory increase in the synthesis of hydroxymethylglutaryl-CoA reductase which leads to augmented hepatic de novo cholesterol synthesis and subsequent increased cholesterol output followed by an increase in the lithogenicity of bile. CS-514 apparently does not prevent cholesterol gallstone formation in those examples where the mechanism is thought to be due to augmented hepatic de novo cholesterol synthesis (type IV hyperlipidemia).     

Alpha-asarone inhibits HMG-CoA reductase, lowers serum LDL-cholesterol levels and reduces biliary CSI in hypercholesterolemic rats.

Our results showed that alpha-asarone was an inhibitor of hepatic HMG-CoA reductase and that the administration of alpha-asarone at 80 mg/kg body wt. for 8 days decreased serum cholesterol by 38% (p < 0.001) in hypercholesterolemic rats. This alpha-asarone treatment affected mainly the serum LDL-cholesterol levels, leaving serum HDL-cholesterol lipoproteins unaffected, with a consequent decrease of 74% in the LDL/HDL ratio. In addition, alpha-asarone especially stimulated bile flow in hypercholesterolemic rats (60%), increasing the secretion of bile salts, phospholipids and bile cholesterol. The drug also reduced the cholesterol levels of gallbladder bile, whereas the concentration of phospholipids and bile salts increased only slightly, leading to a decrease in the cholesterol saturation index (CSI) of bile in the hypercholesterolemic rats. This CSI decrease and the increase in bile flow induced by alpha-asarone may account for the cholelitholytic effect of alpha-asarone. It seems that alpha-asarone induced clearance of cholesterol from the bloodstream and that the excess of hepatic cholesterol provided by LDL-cholesterol is diverted to bile sterol secretion via a bile choleresis process. The inhibition of HMG-CoA reductase and the increase in bile flow induced by alpha-asarone, as well as the decrease in the CSI, could then explain the hypocholesterolemic and cholelitholytic effects of alpha-asarone.     

Intestinal HMG-CoA reductase activity is low in hypercholesterolemic patients and is further decreased with lovastatin therapy

Significant cholesterol synthesis occurs in gut mucosa of animals and humans. However, the role of gut synthesis in hypercholesterolemia and the effect of drugs on this function have not been defined. We obtained jejunal biopsies and bile samples from 21 Type II hypercholesterolemic subjects (mean serum cholesterol = 331 mg/dl) on a low fat diet after an over-night fast. Whole gut mucosal homogenate was assayed for activity of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, the rate-determining enzyme of cholesterol synthesis. Mean reductase activity (pmol/mg per min) was 5.5 +/- 1.0 (n = 21) in hypercholesterolemic subjects versus 11.3 +/- 1.0 in 52 normal subjects (P less than 0.01). This is consistent with the hypothesis that the primary defect in these patients is not excessive cholesterol synthesis but decreased low density lipoprotein (LDL) clearance. It implies that high LDL levels down-regulate gut reductase activity. After treatment of 7 patients with lovastatin (40-80 mg/day for at least 6-13 weeks), gut reductase activity decreased from 7.7 +/- 2.6 to 3.6 +/- 0.5 (P less than 0.05), in biopsies obtained 12 hr after the last drug dose. Inhibition of reductase activity by this drug was detected 12 hr after a dose, and the enzyme was not measurably induced during 6-13 weeks of therapy. In keeping with the decrease in serum cholesterol (332----239 mg/dl) and mucosal reductase activity during lovastatin therapy, mean gallbladder bile cholesterol saturation index also decreased (1.045 +/- 0.112 vs. 0.883 +/- 0.109, n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)     

CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species

CS-514 is a tissue-selective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a key enzyme in cholesterol synthesis. For the microsomal enzyme from rat liver, the mode of inhibition is competitive with respect to hydroxymethylglutaryl-CoA, and the Ki value is 2.3 X 10(-9) M. CS-514 also strongly inhibited the sterol synthesis from [14C]acetate in cell-free enzyme systems from rat liver and in freshly isolated rat hepatocytes; the concentrations required for 50% inhibition were 0.8 ng/ml and 2.2 ng/ml, respectively. On the other hand, the inhibition by CS-514 was much less in the cells from nonhepatic tissues such as freshly isolated rat spleen cells, and cultured mouse L cells and human skin fibroblasts. In addition, the cellular uptake of 14C-labeled CS-514 by isolated rat spleen cells or mouse L cells was less than one-tenth of that by isolated hepatocytes. These differences between hepatic and nonhepatic cells were further confirmed by the fact that CS-514 orally administered to rats inhibited sterol synthesis selectively in liver and intestine, the major sites of cholesterogenesis. CS-514 markedly reduced serum cholesterol levels in dogs, monkeys and rabbits, including Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia in man, but did not reduce those in rats and mice. In the former case, preferential lowering of atherogenic lipoproteins was observed in all of the animals tested. The biliary neutral sterols significantly decreased, whereas the amount of biliary bile acids was not affected by administration of the drug to dogs.     

Hypolipidaemic efficacy of Capparis decidua fruit and shoot extracts in cholesterol fed rabbits

High fat diet caused significant (8-fold) increase in serum total cholesterol in rabbits. Administration of C. decidua fruit extract (50% ethanolic) at the dose of 500 mg/kg body weight significantly reduced serum total cholesterol (61%), LDL cholesterol (71%), triglycerides (32%) and phospholipids (25%). Similarly C. decidua shoot extract lowered serum total cholesterol (48%), LDL cholesterol (57%), triglycerides (38%) and phospholipids (36%).The cholesterol content of aorta was decreased by 44 and 28% in fruit and shoot extract treatment respectively. The HDL to total cholesterol ratio and atherogenic index was significantly decreased in plant extract treated groups suggesting antiatherosclerotic nature of these plant extract. These results reveal the hypolipidaemic potential of C. decidua fruit and shoot.     

Enterostatin (VPDPR) and its peptide fragment DPR reduce serum cholesterol levels after oral administration in mice

We found that enterostatin (VPDPR), an anorexigenic peptide for a high-fat diet, significantly reduces serum cholesterol levels after oral administration of 100 mg/kg for 3 days in mice fed a high cholesterol-cholic acid diet. DPR, a peptide fragment of VPDPR, also had hypocholesterolemic activity at a dose of 50 mg/kg. Food intake was not suppressed under these dietary conditions. Fecal excretion of cholesterol and bile acids was increased significantly by both VPDPR and DPR. Interestingly, DPR induced hypocholesterolemic effects just two hours after a single oral administration at a dose of 100 mg/kg.     

Enterostatin (VPDPR) and Its Peptide Fragment DPR Reduce Serum Cholesterol Levels after Oral Administration in Mice

We found that enterostatin (VPDPR), an anorexigenic peptide for a high-fat diet, significantly reduces serum cholesterol levels after oral administration of 100 mg/kg for 3 days in mice fed a high cholesterol-cholic acid diet. DPR, a peptide fragment of VPDPR, also had hypocholesterolemic activity at a dose of 50 mg/kg. Food intake was not suppressed under these dietary conditions. Fecal excretion of cholesterol and bile acids was increased significantly by both VPDPR and DPR. Interestingly, DPR induced hypocholesterolemic effects just two hours after a single oral administration at a dose of 100 mg/kg.     

The use of ginger (Zingiber officinale Rosc.) as a potential anti-inflammatory and antithrombotic agent

The effect of an aqueous extract of ginger (Zingiber officinale) on serum cholesterol and triglyceride levels as well as platelet thromboxane-B(2) and prostaglandin-E(2) production was examined. A raw aqueous extract of ginger was administered daily for a period of 4 weeks, either orally or intraperitoneally (IP) to rats. Fasting blood serum was investigated for thromboxane-B(2), prostaglandin-E(2), cholesterol and triglycerides. A low dose of ginger (50 mg/kg) administered either orally or IP did not produce any significant reduction in the serum thromboxane-B(2) levels when compared to saline-treated animals. However, ginger administered orally caused significant changes in the serum PGE(2) at this dose. High doses of ginger (500 mg/kg) were significantly effective in lowering serum PGE(2) when given either orally or IP. However, TXB(2) levels were significantly lower in rats given 500 mg/kg ginger orally but not IP. A significant reduction in serum cholesterol was observed when a higher dose of ginger (500 mg/kg) was administered. At a low dose of ginger (50 mg/kg), a significant reduction in the serum cholesterol was observed only when ginger was administered IP. No significant changes in serum triglyceride levels were observed upon administration of either the low or high dose of ginger. These results suggest that ginger could be used as an cholesterol-lowering, antithrombotic and anti-inflammatory agent.     

Endogenous oxytocin excites phasic contraction of gallbladder in rabbits through oxytocin receptor

These experiments were performed to study the effect of oxytocin (OT) and it's specific receptor on gallbladder motility in rabbits. The fasted New Zealand white rabbits (2.0-2.5 kg) were anaesthetized by urethane (1 g/kg). The gallbladder pressure was recorded continuously to monitor the gallbladder motility. Systemic OT (0.01, 0.02, 0.04 mg/kg, iv) did not affect the gallbladder pressure, but dose-dependently increased the frequency of phasic contraction. Five min after OT administration (0.04 mg/kg, iv), the strength of phasic contraction increased to 0.23 +/- 0.08 mmHg/min (P < 0.01, n = 6). The gallbladder motility returned to normal 15 min later after OT treatment. Intravenous injection of atosiban (0.04 mg/kg, iv), an OT receptor antagonist, decreased the strength of gallbladder phasic contraction but did not affect gallbladder pressure. Pretreatment of atosiban (0.04 mg/kg, iv) completely abolished the systemic OT effect on gallbladder. Vasopressin (VP) (0.1 - 0.5 IU/kg, iv) dose-dependently decrease the gallbladder pressure but did not affect the phasic contraction. MK-329 (0.4 mg/kg, iv), the CCK-A receptor antagonist, L-365, 260 (0.4 mg/kg, iv), the CCK-B receptor antagonist and atropine (0.2 mg/kg, iv), the M receptor antagonist, did not affect the OT effect on gallbladder motility. We suggest that endogenous OT regulates gallbladder phasic contraction through specific OT receptor. This effect is independent of the peripheral CCK and M receptors.     

Cholesterol and its lipoprotein fraction in serum and bile of patients with cholelithiasis]

Total cholesterol, HDL, LDL and triglycerides were assayed in the blood serum and bile from the liver and gallbladder of both normal individuals and patients with cholelithiasis. It was found that all assayed parameters are significantly higher in patients with cholelithiasis. An increase in total cholesterol and HDL was seen in the bile from the liver whereas an increase in the level of unstable LDL by about four fold with simultaneous decrease in HDL level were found in the bile from the gallbladder. These differences in lipoprotein fractions level in patients with cholelithiasis indicate systemic disorders in cholesterol metabolism.     

Effect of bromocriptine on lipid plasma levels in rats

Results show that bromocriptine induced marked alterations in plasma levels of cholesterol and lipids in response to acute and chronic administrations in rats. Two hours after an I.P. dose of 10 mg/kg, bromocriptine mesylate caused significant reductions in plasma levels of total high density lipoprotein (HDL) and high density lipoprotein cholesterol (HDL cholesterol). At a dose of 20 mg/kg, bromocriptine mesylate induced significant elevations in plasma levels of total cholesterol, total HDL, HDL cholesterol, total low density lipoproteins (LDL), and low density lipoprotein cholesterol (LDL cholesterol). Injected at a dose of 4 or 10 mg/kg daily for 14 consecutive days, bromocriptine mesylate caused significant increases in plasma levels of total cholesterol, LDL cholesterol and total LDL whereas the levels of HDL cholesterol, total HDL triglycerides (TG) were reduced. At a dose of 20 mg/kg all parameters were significantly increased. Marked hyperglycaemia was noticed in response to doses of 10, 15 and 20 mg/kg injected daily for 14 consecutive days or 2 hrs after a single administration of 15 mg/kg. Plasma insulin activity was reduced 2 hours after injection of bromocriptine at a dose of 15 mg/kg Likewise, a significant reduction in plasma insulin activity was observed in response to daily I.P. injections of bromocriptine at a dose of 15 mg/kg. Hyperglycaemic and hypoinsulinaemic effects of bromocriptine (acute and chronic) were markedly decreased when sulpiride, a dopaminergic D2 antagonist, was injected at an I.P. dose of 10 mg/kg before bromocriptine. Plasma ACTH activity was significantly increased in response to bromocriptine (15 mg/kg I.P.) in acute and chronic experiments. This effect was markedly diminished when sulpiride was injected prior to bromocriptine. In conclusion, bromocriptine induced marked elevations in plasma levels of total cholesterol and lipids which are likely to be related to hyperglycaemic and hypoinsulinaemic effects.     

Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE-/- mice by SC-435

Blocking intestinal bile acid absorption by inhibiting the apical sodium codependent bile acid transporter (ASBT) is a target for increasing hepatic bile acid synthesis and reducing plasma LDL cholesterol. SC-435 was identified as a potent inhibitor of ASBT (IC50 = 1.5 nM) in cells transfected with the human ASBT gene. Dietary administration of 3 mg/kg to 30 mg/kg SC-435 to apolipoprotein E-/- (apoE-/-) mice increased fecal bile acid excretion by >2.5-fold. In vivo inhibition of ASBT also resulted in significant increases of hepatic mRNA levels for cholesterol 7alpha-hydroxylase and HMG-CoA reductase. Administration of 10 mg/kg SC-435 for 12 weeks to apoE-/- mice lowered serum total cholesterol by 35% and reduced aortic root lesion area by 65%. Treatment of apoE-/- mice also resulted in decreased expression of ileal bile acid binding protein and hepatic nuclear hormone receptor small heterodimer partner, direct target genes of the farnesoid X receptor (FXR), suggesting a possible role of FXR in SC-435 modulation of cholesterol homeostasis. In dogs, SC-435 treatment reduced serum total cholesterol levels by 相似文献   

Antiatherogenic effect of taurine in high fat diet fed rats

The role of taurine on atherogenesis induced by high fat diet in rats, a species which depends entirely on taurine for conjugation of bile acids has been investigated. Wistar male rats were fed on (p.o.) taurine in addition to high fat diet (11% coconut oil w/w) for 6 months. High fat diet caused significant increase of serum total cholesterol (2 fold), serum triglycerides (92.6%), LDL cholesterol (92.3%) and body weight gain (2.8 fold). Taurine administration significantly reduced serum cholesterol (37%), triglycerides (94.5%), LDL cholesterol (34%), body weight (46%). It also significantly reduced aortic cholesterol and thiobarbituric acid reactive substances and there was a significant increase of reduced glutathione. Taurine significantly increased fecal bile acids which may have resulted in significant decrease of serum cholesterol. Aortic lesion index was significantly decreased in the taurine administered group suggesting the antiatherogenic effect of taurine. It is concluded that taurine attenuated the atherogenesis possibly by its hypocholesterolemic and antioxidant property.     

Metabolic effect at six and twelve months of cyproterone acetate (2 mg) combined with ethinyl estradiol (35 micrograms) in 31 patients

The metabolic effects of cyproterone acetate (2 mg) combined with a new dose level of ethinyl estradiol (35 micrograms) were studied over a one-year period in 31 patients presenting moderate clinical hyperandrogenism. The following tests were performed before treatment, at 6 and 12 months, an oral glucose tolerance test (OGTT) with measurement of insulinemia, total cholesterol, HDL cholesterol and the LDL + VLDL/HDL ratio, A1 and B apoproteins. At six months and at one year of treatment, the weight and body mass index (kg/m2) were not modified. Glucose tolerance and insulinemia had not changed significantly at one year. Lipid test results showed an increase in triglycerides, as well as in total and HDL cholesterol levels. However, the LDL + VLDL/HDL and A1/B apoprotein ratios did not change during the study. We conclude from these results that the new combination does not have any adverse effects on glucose tolerance and has a predominantly estrogenic effect on lipid parameters, characterized by increases in total cholesterol, HDL cholesterol and triglycerides.     

Inhibition of both the apical sodium-dependent bile acid transporter and HMG-CoA reductase markedly enhances the clearance of LDL apoB

Discovery of the ileal apical sodium-dependent bile acid transporter (ASBT) permitted development of specific inhibitors of bile acid reabsorption, potentially a new class of cholesterol-lowering agents. In the present study, we tested the hypothesis that combining the novel ASBT inhibitor, SC-435, with the HMG-CoA reductase inhibitor, atorvastatin, would potentiate reductions in LDL cholesterol (LDL-C) and LDL apolipoprotein B (apoB). ApoB kinetic studies were performed in miniature pigs fed a typical human diet and treated with the combination of SC-435 (5 mg/kg/day) plus atorvastatin (3 mg/kg/day) (SC-435+A) or a placebo. SC-435+A decreased plasma total cholesterol by 23% and LDL-C by 40%. Multicompartmental analysis (SAAM II) demonstrated that LDL apoB significantly decreased by 35% due primarily to a 45% increase in the LDL apoB fractional catabolic rate (FCR). SC-435+A significantly decreased hepatic concentrations of free cholesterol and cholesteryl ester, and increased hepatic LDL receptor mRNA consequent to increased cholesterol 7alpha-hydroxylase expression and activity. In comparison, SC-435 (10 mg/kg/day) monotherapy decreased LDL apoB by 10% due entirely to an 18% increase in LDL apoB FCR, whereas atorvastatin monotherapy (3 mg/kg/day) decreased LDL apoB by 30% due primarily to a 22% reduction in LDL apoB production. We conclude that SC-435+A potentiates the reduction of LDL-C and LDL apoB due to complementary mechanisms of action.     

Effect of taurine on cholesterol metabolism in hamsters: up-regulation of low density lipoprotein (LDL) receptor by taurine

The effects of taurine on hepatic cholesterol metabolism were investigated in hamsters fed a high-fat diet or normal chow. Two weeks-treatment of taurine at 1% in drinking water prevented high-fat diet-induced increase in cholesterol levels of serum and liver. The decrease in serum cholesterol by taurine was due to decrease in non-HDL cholesterols. A similar tendency was noted in serum and liver cholesterol levels of hamsters fed a normal diet. In hamsters fed a high-fat diet, taurine prevented elevation in hepatic activity of acyl-CoA:cholesterol acyltransferase (ACAT) and increased the activity of cholesterol 7alpha-hydroxylase. Taurine also increased cholesterol 7alpha-hydroxylase activity in hamsters fed normal chow. Studies on liver membranes revealed that taurine increased 125I-labeled LDL binding by 52% and 58% in hamsters fed either a normal chow or high-fat diet, respectively. Furthermore, LDL kinetic analysis showed that taurine intake resulted in significant faster plasma LDL fractional catabolic rates (FCR). These results suggest that taurine elevates hepatic LDL receptor and thereby decreases serum cholesterol levels, an event which may be the result of hepatic cholesterol depletion as a consequence of increased bile acid synthesis via enhancement of cholesterol 7alpha-hydroxylase activity. Thus, up-regulation of the LDL receptor and subsequent increase in receptor- mediated LDL turnover may be a key event in the cholesterol-lowering effects of taurine in hamsters.     

Ileal bile acid transporter inhibition,CYP7A1 induction,and antilipemic action of 264W94

264W94 was designed to inhibit the ileal bile acid transporter (IBAT). Evaluated in vitro, 264W94 dose-dependently inhibited sodium-dependent uptake of 10 micro M [(3)H]taurocholic acid (TC) by rat and monkey brush border membrane vesicles with IC(50)s of 0.24 micro M and 0.41 micro M, and had a competitive profile with K(i) of 0.2 micro M against TC in Chinese hamster ovary cells expressing human IBAT. In distal ileum in situ, 1-10 micro M of 264W94 rapidly decreased uptake of 3mM TC by 24-39%, with corresponding decreases in biliary recovery. In rats and mice in vivo, oral 264W94 decreased absorption of TC analog, 23,25-(75)Se-homocholic acid taurine ((75)SeHCAT; quantitated in feces), with ED(30) of 0.02 mg/kg bid. (75)SeHCAT traced through the GI-tract revealed that peak (97%) inhibition of (75)SeHCAT absorption by the distal quarter of small intestine occurred at 4 h after single dose of 264W94 (0.1 mg/kg). Inhibition of IBAT by 264W94 in rats was associated with compensatory, same-day, 4-fold induction of hepatic cholesterol 7alpha-hydroxylase (CYP7A1) activity, exhibiting normal diurnal fluctuation for 3 days of dosing. In diet induced hypercholesterolemic rats, 264W94 (0.03-1.0 mg/kg bid) dose-dependently reduced serum LDL+VLDL cholesterol up to 61%. In conclusion, 264W94 is a potent new cholesterol lowering agent that acts through inhibition of IBAT and exhibits activity in a human model.     

Copper supplementation effects on indicators of copper status and serum cholesterol in adult males

Two 6-wk double-blind studies evaluated the effects of supplements of 2 or 3 mg Cu/d on serum copper, ceruloplasmin, red-blood-cell super oxide dismutase (RBC-SOD), total serum cholesterol, and serum lipoprotein-cholesterol fractions in adult males. Study I had 6 supplemented and 8 placebo subjects, whereas study II had 7 and 6, respectively. Copper supplementation did not appear to affect serum copper levels, RBC-SOD, hematocrit, and ceruloplasmin levels when assayed by radial immunoassay diffusion. Supplementation with 2 mg Cu/d produced an increase in LDL cholesterol and the percentage of cholesterol as LDL at wk 4 compared to the placebo group, and a concomitant decline in VLDL-cholesterol levels and the percentage of cholesterol as VLDL. At wk 6, the percentage of cholesterol as LDL increased and that of cholesterol as VLDL decreased compared to baseline values in the supplemented group. Supplements of 3 mg Cu/d increased hemoglobin levels, ceruloplasmin activity, and serum total-cholesterol levels at wk 6 compared to placebos. Differences in cholesterol may be partly explained by variability in the placebo groups in both studies. Copper supplementation effects on cholesterol deserves further investigation.