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PubMed1991

Dietary regulation of maternal and fetal cholesterol metabolism in the guinea pig.

Studies to determine the effects of pre-natal interventions on maternal and fetal cholesterol homeostasis were carried out in the guinea pig. Guinea pig dams were fed either non-purified guinea pig diet or diet supplemented with either 1.1% of the bile acid binding resin cholestyramine or 0.25% cholesterol. Whole body rates of endogenous cholesterol synthesis were determined by quantitation of [3H]water incorporation into digitonin precipitable sterols in non-pregnant animals and at 40 and 60 days of gestation in the dam and fetus. Maternal hepatic cholesterol synthesis was reduced 87% by dietary cholesterol and was increased 3.5-fold with cholestyramine feeding. Fetal hepatic and peripheral tissue cholesterol synthesis rates peaked at 40 days gestation when peripheral tissue cholesterol synthesis was 5.7-fold higher and hepatic synthesis 6.2-fold greater than the near adult levels observed at 60 days. Cholesterol synthesis in the fetus was relatively insensitive to dietary manipulations; however, maternal cholestyramine treatment did result in a 1.4-fold increase in fetal carcass cholesterol synthesis at 60 days gestation. These data demonstrate that maternal cholesterogenic systems maintain responsiveness to dietary regulation during pregnancy; whereas fetal cholesterol homeostasis is relatively insensitive to dietary cholesterol throughout gestation yet may respond to induction by maternal cholestyramine treatment during the late gestation period.

Animals↗

PubMed1994

In vivo regulation of hepatic lipase activity and mRNA levels by diets which modify cholesterol influx to the liver.

The aim of this study was to assess whether diets enriched in cholesterol, sodium cholate and drugs known to modify liver cholesterol biosynthesis can modulate hepatic lipase (H-TGL) expression and activity in vivo. Female lean Zucker rats, known to be good responders to cholesterol, were fed for 7 days with a control C diet or the C diet supplemented (w/w) with either 2% cholesterol, 0.5% sodium cholate, 2% cholestyramine or simvastatin (0.1%) added to the cholestyramine diet or given by gavage (10 mg/rat) for 3 days. H-TGL activity decreased by 34% with cholesterol, and by 27% when both cholesterol and cholate were administered to the rats. Under these conditions, H-TGL mRNA decreased by 34% and 87%, respectively. The sharp decrease in H-TGL expression was associated with a strong increase in cholesteryl ester in total liver and in the liver microsome fraction. H-TGL activity decreased by 33% with cholestyramine and the mRNA level decreased by 47%. Simvastatin lowered H-TGL activity by 55% when added to the cholestyramine diet, probably because of a reduction in food intake. When administrated by gavage, simvastatin increased both the H-TGL activity (by 28%) and mRNA (by 23%). These variations may be linked to the availability of mevalonate-derived sterol and non-sterol products.

Animals↗

PubMed1988

Regulation of the release of cholecystokinin by bile salts in dogs and humans.

The objective of these studies was to investigate the role of bile salts in the regulation of release of cholecystokinin in response to nutrients in dogs and humans. In dogs, the intraduodenal administration of a bile salt sequestrant, cholestyramine (2, 4, or 8 g/h), resulted in a dose-related enhancement of the release of cholecystokinin-33/39 and pancreatic protein secretion in response to intraduodenal administration of amino acids. Intraduodenal administration of cholestyramine alone did not affect basal levels of cholecystokinin-33/39 or pancreatic protein secretion. Total diversion of bile also significantly increased the release of cholecystokinin and pancreatic protein secretion in response to intraduodenal administration of amino acids. Replacement of the bile salt pool by intraduodenal administration of taurocholate completely reversed the enhancement effect of both cholestyramine and bile diversion. In humans, oral ingestion of cholestyramine (12 g) significantly increased the release of cholecystokinin-33/39 and gallbladder contraction in response to the oral ingestion of either a triglyceride or amino acids. These results support a physiologic role of bile salts in the negative feedback regulation of release of cholecystokinin in response to luminal nutrients.

Adult↗

PubMed1994

Effect of bile salt binding or protease inactivation on plasma cholecystokinin and gallbladder responses to bombesin.

BACKGROUND/AIMS: Bombesin-stimulated plasma cholecystokinin levels decrease after an initial increase despite continuous infusion of bombesin. The aim of this study was to determine if a feedback mechanism, mediated by bile salts or proteolytic enzymes, is responsible for this decline. METHODS: Bombesin (1.0 ng.kg-1.min-1) was infused into volunteers for 180 minutes on separate occasions. Cholestyramine, colestipol, camostate, or saline were perfused intraduodenally during the second hour of the tests. Cholestyramine was also administered without infusion of bombesin. RESULTS: Colestipol and cholestyramine, dependent on their bile salt-binding capacity, markedly enhanced (P < 0.05) bombesin-stimulated plasma cholecystokinin from 2.1 +/- 0.5 pmol/L to 6.4 +/- 2.2 pmol/L and 12.1 +/- 3.3 pmol/L (P < 0.05 vs. colestipol), respectively, and further decreased gallbladder volume (P < 0.05) from 9.4 +/- 1.6 mL to 2.0 +/- 0.4 mL and 2.2 +/- 0.5 mL, respectively. The protease inhibitor camostate had no effect. Bile salt precipitation also enhanced plasma pancreatic polypeptide responses (P < 0.01) but did not alter gastrin responses. Plasma cholecystokinin responses to cholestyramine without bombesin infusion varied considerably, but increments were highly correlated to decreases in gallbladder volume (r = 0.91; P < 0.005). CONCLUSIONS: Bile salt sequestration but not protease inactivation enhances plasma cholecystokinin and gallbladder responses to bombesin infusion in humans.

Adult↗

PubMed1998

Endogenous cholecystokinin enhances postprandial gastroesophageal reflux in humans through extrasphincteric receptors.

BACKGROUND & AIMS: Exogenous cholecystokinin (CCK) decreases lower esophageal sphincter (LES) pressure and increases transient LES relaxations (TLESRs) in humans. The aims of this study were to determine whether endogenous CCK increases gastroesophageal reflux in humans and whether this is a direct effect on the LES. METHODS: Esophageal pH, LES pressure, and gallbladder volume were measured in 8 healthy volunteers after ingestion of a 181-kcal meal alone or adding 12 g cholestyramine to increase endogenous CCK release. In 7 additional volunteers, the effect of cholestyramine was studied during intravenous perfusion of saline or the CCK-A receptor antagonist loxiglumide. In circular LES strips from 9 transplant donors, we measured the effect of CCK-8 (10(-11) to 3 x 10(-8) mol/L) on basal tension and on electrical field-induced relaxation. RESULTS: Cholestyramine increased gallbladder emptying, reflux episodes, TLESRs, and time of esophageal pH of <4. Loxiglumide inhibited postprandial gallbladder emptying, reflux episodes, TLESRs, and time of pH of <4 and prevented the decrease in LES pressure induced by cholestyramine. In vitro, CCK-8 contracted LES strips through a tetrodotoxin-insensitive pathway but did not modify electrical field-induced LES relaxations. CONCLUSIONS: Endogenous CCK enhances postprandial gastroesophageal reflux in humans by increasing the rate of TLESRs and reduces postprandial LES pressure. These actions seem mediated by extrasphincteric CCK-A receptors that override a direct contractile effect of CCK on the LES muscle.

Adult↗

PubMed1977

Dose-effect relation of cholestryamine in children and young adults with familial hypercholesterolaemia.

Twenty children and young adults with familial hypercholesterolaemia (F.H.), on a diet low in cholesterol and high in polyunsaturated fats, were treated with cholestyramine in a metabolic unit to determine the decrease in plasma cholesterol and low-density lipoprotein (L.D.L.) cholesterol in relation to drug dosage, pretreatment concentrations of cholesterol and L.D.L. cholesterol, and body-weight. When the dose of cholestyramine was increased in thirteen patients by 1 g/day up to 16 g/day, given twice daily, cholesterol and L.D.L. cholesterol fell within the normal range in eleven subjects (average dose, 7 g/day), and the response was directly proportional (P less than less than 0-001) to the pretreatment concentrations of cholesterol (r = 0-89) and L.D.L. cholesterol (r = 0-93) but did not correlate with body-weight. Plasma total cholesterol and L.D.L. cholesterol continued to fall and concentrations reached a plateau after which additional cholestyramine had no further effect (average dose, 11 g/day). The L.D.L. cholesterol regression line successfully predicted the dose required to reduce L.D.L. cholesterol concentrations in seven other patients. There was a significant decrease in mean serum-folate in female patients. It was concluded that the minimum effective dose of cholestyramine in young patients with F.H. can be predicted from the pretreatment plasma total and L.D.L. cholesterol and may be given twice daily.

Administration, Oral↗

PubMed1998

Lowering of serum cholesteryl ester transfer protein--but not lecithin:cholesterol acyltransferase--activity levels by hypocholesterolemic drugs in the rabbit.

Cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT) are important factors in the regulation of serum lipoprotein metabolism. Rabbits were fed hypocholesterolemic drugs to investigate the effect on serum CETP and LCAT activity levels. The activities were assayed using exogenous substrate assays and are an estimate of CETP and LCAT mass. Groups of eight rabbits were fed a cholesterol-free diet containing either 0.03% simvastatin or 1% cholestyramine for 6 weeks. For comparison eight rabbits were fed a cholesterol-free control diet without drugs or a diet containing 0.1% cholesterol for 6 weeks. Total serum and lipoprotein triglyceride concentrations were not different after intervention with the hypocholesterolemic drugs or the cholesterol diet. Dietary cholesterol induced higher VLDL, IDL, and LDL cholesterol, as well as serum CETP activity, as expected. Serum LCAT activity showed little change with intervention. Both simvastatin and cholestyramine tended to lead to decreased cholesterol in all lipoprotein fractions and caused a significant decrease in serum CETP activity when compared with the control diet. Both drugs also caused a significant lower LDL particle concentration, as judged from differences in LDL protein levels. Intervention with simvastatin or cholestyramine led to relatively cholesterol-poor LDL. These effects on LDL concentration and composition were opposite from the effects of cholesterol feeding. Differences in the cholesterol contents of VLDL and IDL were comparable with those in LDL. The results suggest that decreasing serum CETP activity levels by treatment with simvastatin or cholestyramine may contribute to lowering of cholesterol apo B-containing lipoproteins. The effects are additional to the well-known increase in hepatic LDL receptor activity, which is likely to be the most important factor in LDL cholesterol lowering by these drugs.

Animals↗

PubMed1998

Ca2+ mobilization in the aortic endothelium in streptozotocin-induced diabetic and cholesterol-fed mice.

1. Experiments were performed to compare Ca2+ mobilization in the aortic endothelium in streptozotocin (STZ)-induced diabetic and cholesterol-fed mice with that in age-matched controls. 2. The intracellular free Ca2+ ([Ca2+]i) in the fura PE-3 loaded endothelium of aortic rings was dose-dependently increased by cumulative administration of acetylcholine (ACh). ACh caused a transient rise in [Ca2+]i in Ca2+-free medium. The ACh-induced increase in [Ca2+]i in normal or Ca2+-free medium was significantly weaker in both STZ-induced diabetic and cholesterol-fed mice. 3. The weaker [Ca2+]i response in Ca2+-containing medium in STZ-induced diabetic and cholesterol-fed mice was normalized by chronic administration of cholestyramine. 4. The increased low density lipoprotein (LDL) levels seen in both STZ-induced diabetic and cholesterol-fed mice were normalized by the same chronic administration of cholestyramine (300 mg kg(-1), p.o. daily for 10 weeks). Chronic administration of cholestyramine had no effect on the plasma glucose level. 5. Lysophosphatidylcholine (LPC) decreased the [Ca2+]i responses to ACh in the aortic endothelium from normal mice. 6. These results suggest that ACh increases both Ca2+ influx and Ca2+ release from storage in the aortic endothelium. The weaker [Ca2+]i influx seen in the endothelium of aortae from both STZ-induced diabetic and cholesterol-fed mice was improved by the chronic administration of cholestyramine, and we suggest that this improvement is due, at least in part, to a lowering of the plasma LDL level. It is further suggested that LPC may have an important influence over Ca2+ mobilization in the endothelium.

Animals↗

PubMed2000

Acute intraduodenal bile salt depletion leads to strong gallbladder contraction, altered antroduodenal motility and high plasma motilin levels in humans.

Cholecystokinin is the main hormone involved in postprandial gallbladder contraction. There is also considerable gallbladder contraction in the fasting state, associated with phase III of the gastrointestinal migrating motor complex and release of the hormone motilin. It has been proposed that intraduodenal bile salts exert a negative-feedback control on postprandial cholecystokinin release and resulting gallbladder contraction. We wanted to elucidate whether a similar control mechanism on gallbladder contraction exists in the fasting state. We therefore performed gallbladder ultrasonography and 24-h antroduodenal motility registrations and determined plasma cholecystokinin and motilin levels in six healthy subjects before and after acute (4 g) and chronic (8 days; 8 g day(-1)) oral cholestyramine. Acute cholestyramine strongly decreased gallbladder volumes and increased motilin without changed cholecystokinin levels. There was a negative relationship between gallbladder volumes and plasma motilin levels. Although there was a persistent fasting pattern of antroduodenal motility, its cycle length was increased (P < 0.03) with markedly longer phase II (P < 0. 005). Fasting gallbladder volumes 24 h later were still strongly decreased but gradually increased to pretreatment levels. Before and after 8 days cholestyramine, interdigestive and postprandial gallbladder emptying, intestinal migrating motor complex and hormone levels did not differ. We conclude that acute (but not chronic) intraduodenal bile salt depletion with cholestyramine affects gallbladder and antroduodenal motility, possibly partly related to motilin release.

Adult↗

PubMed2003

Influence of newly synthesized cholesterol on bile acid synthesis during chronic inhibition of bile acid absorption.

The effects of newly synthesized cholesterol availability on bile acid synthesis are largely unknown, particularly in humans. The present study was aimed to study the changes induced on bile acid synthesis by simvastatin, a competitive inhibitor of hydroxymethyl glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme of cholesterol synthesis, during pharmacologic interruption of the enterohepatic circulation. Six patients with primary hypercholesterolemia were studied in basal conditions, after treatment with the bile acid binding resin cholestyramine alone (8-16 g/d for 6-8 weeks) and subsequently in combination with simvastatin (40 mg/d for 6-8 weeks). Cholesterol 7alpha-hydroxylation rate, a measure of total bile acid synthesis, was assayed in vivo by tritium release analysis. Serum lathosterol levels were assayed by gas chromatography-mass spectrometry as a measure of cholesterol synthesis. Serum total and low-density lipoprotein-cholesterol were reduced significantly after cholestyramine (by 26% and 30%, respectively) and during combined treatment (by 47% and 55%). 7alpha-hydroxylation rates increased nearly 4-fold with cholestyramine alone; addition of simvastatin induced a significant decrease of hydroxylation rates (cholestyramine alone, 1,591 +/- 183 mg/d; plus simvastatin, 1,098 +/- 232 mg/d; mean +/- SEM; P <.05). Hydroxylation rates significantly correlated with serum lathosterol/cholesterol ratio (r = 0.79, P <.05). In conclusion, in conditions of chronic stimulation bile acid synthesis may be affected by changes in newly synthesized cholesterol availability. The finding might relate to the degree of substrate saturation of microsomal cholesterol 7alpha-hydroxylase; alternatively, newly synthesized cholesterol might induce a stimulatory effect on cholesterol 7alpha-hydroxylase transcription.

Absorption↗

PubMed1993

The effect of non-starch polysaccharide supplementation on circulating bile acids, hormone and metabolite levels following a fat meal in human subjects.

The effects of guar gum, sugar-beet fibre (SBF) and wheat bran supplementation of a high-fat test meal were compared with an NSP-free control meal and a meal containing an equivalent amount of the ion-exchange resin cholestyramine in healthy non-obese human volunteers. Their effects on gastric emptying, postprandial circulating bile acids, triacylglycerols and gastrointestinal hormone levels were studied. The in vitro binding of NSP and cholestyramine to [1-14C]glycocholic acid was measured and compared with their in vivo effect. Guar gum and cholestyramine supplementation significantly lowered circulating postprandial bile acid, triacylglycerol and gastric inhibitory polypeptide concentrations, but sugar-beet fibre and wheat bran were without effect. Liquid gastric emptying, as assessed by circulating paracetamol levels, was slightly accelerated in the guar gum-supplemented meal. Glycocholic acid bound strongly to the insoluble fraction of cholestyramine and the soluble fraction of guar gum. The insoluble fractions of SBF and wheat bran bound only small quantities of glycocholate; no bile acid binding was detected in the soluble fractions of these NSP. The study demonstrates that measurement of postprandial bile acids enables an indirect measurement to be made of bile acid binding to NSP in vivo. The results support the hypothesis that the hypocholesterolaemic action of guar gum is largely mediated via interruption of the enterohepatic bile acid circulation, but indicate that the hypocholesterolaemic action of SBF is mediated by another mechanism.

Adult↗

PubMed2005

Mechanisms of cholesterol-lowering effects of dietary insoluble fibres: relationships with intestinal and hepatic cholesterol parameters.

Fibres with a range of abilities to perturb cholesterol homeostasis were used to investigate how the serum cholesterol-lowering effects of insoluble dietary fibres are related to parameters of intestinal cholesterol absorption and hepatic cholesterol homeostasis in mice. Cholestyramine, chitosan and cellulose were used as examples of fibres with high, intermediate and low bile acid-binding capacities, respectively. The serum cholesterol levels in a control group of mice fed a high fat/high cholesterol (HFHC) diet for 3 weeks increased about 2-fold to 4.3 mm and inclusion of any of these fibres at 7.5 % of the diet prevented this increase from occurring. In addition, the amount of cholesterol accumulated in hepatic stores due to the HFHC diet was reduced by treatment with these fibres. The three kinds of fibres showed similar hypocholesterolaemic activity; however, cholesterol depletion of liver tissue was greatest with cholestyramine. The mechanisms underlying the cholesterol-lowering effect of cholestyramine were (1) decreased cholesterol (food) intake, (2) decreased cholesterol absorption efficiency, and (3) increased faecal bile acid and cholesterol excretion. The latter effects can be attributed to the high bile acid-binding capacity of cholestyramine. In contrast, incorporation of chitosan or cellulose in the diet reduced cholesterol (food) intake, but did not affect either intestinal cholesterol absorption or faecal sterol output. The present study provides strong evidence that above all satiation and satiety effects underlie the cholesterol-lowering properties of insoluble dietary fibres with moderate or low bile acid-binding capabilities.

Animals↗

PubMed1986

Dietary and other correlates of changes in total and low density lipoprotein cholesterol in hypercholesterolemic men: the lipid research clinics coronary primary prevention trial.

Correlates of changes in total (TOTAL-C) and low density lipoprotein cholesterol (LDL-C) were examined in the 3806 hypercholesterolemic men of the Lipid Research Clinics Coronary Primary Prevention Trial. These correlates included changes in weight, dietary and alcohol intake, plasma glucose and thyroxine, cigarette smoking, packet count, lipid-lowering drugs other than cholestyramine, and antihypertensive drugs. In both placebo plus diet and cholestyramine plus diet treatment groups, decreases in Quetelet index and in saturated fat and cholesterol intake and increases in polyunsaturated fat intake were consistently associated with reductions in TOTAL-C and in LDL-C. In the cholestyramine group, plasma glucose and smoking were predictors of increased TOTAL-C and LDL-C; age and packet count were predictors of decreased TOTAL-C and LDL-C. Diuretic use was associated with increases in TOTAL-C in both groups and with increases in LDL-C in the cholestyramine group.

Adult↗

PubMed1987

Report on the Lipid Research Clinic trials.

The Lipid Research Clinic Coronary Primary Prevention Trial was a randomized, double-blind, placebo-controlled intervention trial performed in 3806 hypercholesterolaemic (greater than 265 mg dl-1) but asymptomatic men aged 35-59 at entry. The bile acid sequestrant cholestyramine was used to achieve the cholesterol differential in the treatment group. Both groups received a modest low cholesterol-low fat diet. All subjects were followed for at least seven years (mean duration 7.4 years) during which time a mean fall of 8% and 12% in plasma total cholesterol and LDL cholesterol levels respectively relative to levels in placebo controls were achieved and maintained. The cholestyramine group experienced a 19% reduction in risk (P greater than 0.05) of the primary end point-definite coronary heart disease death and/or definite non-fatal myocardial infarction. In addition, the incidence rates for new positive exercise tests, angina, and coronary bypass surgery were all significantly reduced by 25%, 20% and 21%, respectively, in the cholestyramine group. In the treated group, risk reduction was related directly to reduction in total and LDL cholesterol. In a similar but considerably smaller double blind, placebo-controlled, secondary prevention trial where coronary artery lesion change as determined by serial coronary angiography was the end point (The NHLBI Type II Intervention Trial), cholestyramine treatment significantly delayed the progression of atherosclerotic lesions. Plaque progression related directly to both a fall in low density lipoprotein and a rise in high density lipoprotein.

Adult↗

PubMed1996

Hypercholesterolemia with cholesterol-enriched LDL and normal levels of LDL-apolipoprotein B. Effects of the step I diet and bile acid sequestrants on the cholesterol content of LDL.

One form of hypercholesterolemia is characterized by high levels of LDL cholesterol and normal levels of LDL-apolipoprotein (apo) B. The reason for hypercholesterolemia, therefore, is enrichment of LDL particles with cholesterol. We have reported previously that about one third of patients with primary moderate hypercholesterolemia have this lipoprotein pattern and have no apparent abnormality in LDL-apo B metabolism. The current study was designed to determine whether the combination of the Step I Diet (30% of total calories as fat, <10% saturated fatty acids, and <300 mg per day cholesterol) with or without cholestyramine therapy will correct the hypercholesterolemia in patients of this type. Ten hypercholesterolemic men of this type were identified and recruited into the study. Their LDL cholesterol levels were > or = 160 mg/dL and LDL-apo B levels were <120 mg/dL (LDL cholesterol/apo B ratio >1.60). For patient selection, subjects were challenged with a high fat diet (40% of total calories as fat, 18% saturated fatty acids, and 400 mg per day cholesterol) for 6 weeks to confirm persistence of a high LDL cholesterol/apo B ratio. Thereafter, they were started on a Step I Diet, and lipoprotein analyses were repeated. Finally, cholestyramine (16 g per day) was added to the Step I Diet. The Step I Diet alone significantly reduced the LDL cholesterol/apo B ratios and produced a trend toward lowering LDL cholesterol levels. Cholestyramine therapy further reduced LDL cholesterol levels and maintained a normal LDL cholesterol/apo B ratio. The present investigation thus confirms the existence of a form of moderate hypercholesterolemia that arises from a defect in LDL composition. In addition, it demonstrates that the combination of Step I Diet and cholestyramine therapy corrects this defect and normalizes LDL levels and LDL composition.

Aged↗

PubMed1968

Turnover of plasma cholesterol in man.

Cholesterol-4-(14)C was injected intravenously into a series of normal men, untreated hyperlipidemic patients, and hyperlipidemic patients being treated with cholestyramine. The specific radioactivity of plasma total cholesterol was measured during the ensuing 10 wk. 16 studies were carried out in 10 subjects. Analysis of the turnover curves of plasma cholesterol revealed that in every study the turnover of plasma cholesterol conformed to a two-pool model. Each turnover curve was analyzed in terms of this model, as expressed by the equation: specific activity = C(A)e(-alphat) + C(B)e(-betat). The parameters which were calculated included the constants C(A), C(B), alpha, and beta; the size of the first pool (M(A)); the rate constants for the total rate of removal of cholesterol from each pool (k(AA) and k(BB)); and the production rate in pool A (PR(A)). In two normal men and five untreated patients the average size of pool A was 25g. The effect of cholestyramine was assessed by comparing the results obtained without therapy with those obtained during therapy in five subjects studied under both conditions. Cholestyramine therapy produced a large increase in PR(A) (from 0.98 to 1.98 g/day) and in the rate of removal of cholesterol from pool A. Cholestyramine did not significantly alter the size of pool A. It is not possible to calculate the size of the total body exchangeable pool of cholesterol from the turnover curve of plasma cholesterol. It is also not possible to calculate the metabolic turnover rate, i.e., the rate of cholesterol degradation and excretion, in the whole body. This parameter can, however, be estimated by assuming that cholesterol is removed from the body only by way of the tissue pools that comprise pool A. Under these conditions the metabolic turnover rate is equal to the production rate in pool A.

Adult↗

PubMed1990

Protective action of luminal bile salts in necrotizing acute pancreatitis in mice.

Bile salts in the intestinal lumen act to inhibit the release of cholecystokinin (CCK). Recent studies have shown that CCK may play a permissive role in the development of acute pancreatitis. In this study, the amount of luminal bile salts in female Swiss Webster mice was either decreased by feeding 4% (wt/wt) cholestyramine or increased by feeding 0.5% sodium taurocholate for 1 wk. Plasma levels of CCK were stimulated by cholestyramine and inhibited by taurocholate. Then, acute pancreatitis was induced either by caerulein injections, or by feeding a choline-deficient, ethionine-supplemented (CDE) diet. Feeding of cholestyramine significantly decreased survival from 25% to 0% in the CDE pancreatitis, and increased the magnitude of elevation of serum amylase levels and the extent of pancreatic necrosis in both models of pancreatitis; CCK-receptor blockade with CR-1409 completely abolished the adverse effects of cholestyramine. In contrast, feeding of taurocholate significantly increased survival to 100% and decreased the elevation of serum amylase and pancreatic necrosis; CCK-8 antagonized these actions of taurocholate. Luminal bile salts appear to provide a physiologic protection against necrotizing pancreatitis, at least in part, both by inhibiting the release of CCK and by promoting resistance of the pancreas to CCK excessive stimulation in vivo.

Acute Disease↗

PubMed1993

Some effects of chitosan on liver function in the rat.

Chitosan, a natural product derived from chitin, possesses hypocholesterolemic properties similar to those of cholestyramine, but there has been no report concerning its effects on the equilibrium between dietary cholesterol and de novo cholesterol synthesis in the liver. In this work, we studied the effects of chitosan on plasma and liver cholesterol levels, liver weight, and the key regulatory enzyme of cholesterogenesis 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase in rats fed a sterol diet containing 1% cholesterol and 0.2% cholic acid. The animals given the sterol diet showed increases in plasma and liver cholesterol, which were lowered by 54% in plasma and 64% in liver by 5% chitosan, while cholestyramine completely blocked such increases. HMG-CoA reductase activity was considerably increased in the sterol-cholestyramine group, but was greatly decreased in both sterol and sterol-chitosan groups. There was no change in liver weight or appearance after treatment with chitosan, but cholestyramine-treated animals manifested secondary effects from the treatment, including smaller yellowish livers. High mol wt chitosans [> 750 kilodaltons (kDa)] were found to be less effective as hypocholesterolemia than a 70-kDa preparation. Also, when the 70-kDa chitosan was used at 2.5%, 5%, and 7.5% of the total diet, its effectiveness was greatest at the higher concentrations; indeed, incorporation of 7.5% chitosan in the sterol diet for 3 weeks completely prevented any decrease in plasma high density lipoprotein cholesterol or increase in the plasma cholesterol level and liver weight. This formula greatly reduced the increase in liver cholesterol content due to the sterol diet, with values of 8.8 +/- 1.3 for the sterol-chitosan diet vs. 18.2 +/- 0.8 mg/g tissue for the sterol diet. The increased intake of sterols considerably lowered both HMG-CoA reductase activity (33-fold) and HMG-CoA reductase mRNA levels (3-fold) in rat liver, but in the sterol-chitosan group, HMG-CoA reductase activity was 7.7 times more elevated than in the sterol group, although it was still lower than the control value, whereas HMG-CoA reductase mRNA levels were normal. The results obtained did not differ significantly when rats were studied for 1, 3, or 6 weeks. These results taken collectively indicate that the 7.5% chitosan formula maintained adequate cholesterol homeostasis in rats, despite a greatly increased intake of cholesterol.

Animals↗