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PubMed1989

[Influence of pH in the adsorption capacity of bile salts and lysolecithins in vitro by antacids containing clay and/or aluminum].

In vitro binding properties of eight clay and/or aluminium-containing antacids for bile salts and lysolecithin were measured in comparison with cholestyramine binding capacity, taking into account the final medium pH. Dihydroxy-bile salt adsorption was greater when the initial pH was 1.8 and the intensity varied according to the drugs. Trihydroxybile salts were less bound and the binding was less related to the medium pH. Lysolecithins were bound by clay-containing antacids with the same intensity as cholestyramine, while the binding capacity of aluminium-containing antacids was weaker and related to the final pH. There were close relationships between binding capacities and the final pH so that bile salts are bound by antacids with a great intensity in acid medium and released by alkalinisation in contrary to the binding capacity of cholestyramine. Lysolecithins should be also bound more intensively in acid medium by aluminium-containing antacids. Binding capacities of the antacids were related to their composition, their antacid effect and to the final pH.

Adsorption↗

PubMed1986

Regulation of rat liver 3-hydroxy-3-methylglutaryl coenzyme A synthase and the chromosomal localization of the human gene.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase was purified to homogeneity from rat liver cytoplasm. The active enzyme is a dimer composed of identical subunits of Mr = 53,000. The amino acid composition and the NH2-terminal sequence are presented. Partial cDNA clones for the enzyme were isolated by screening of a rat liver lambda gt11 expression library with antibodies raised against the purified protein. The identity of the clones was confirmed by hybrid selection and translation. When rats were fed diets supplemented with cholesterol, cholestyramine, or cholestyramine plus mevinolin, the hepatic protein mass of cytoplasmic synthase, as determined by immunoblotting, was 25, 160, and 1100%, respectively, of the mass observed in rats fed normal chow. Comparable changes in enzyme activity were observed. Approximately 9-fold increases in both HMG-CoA synthase mRNA mass and synthase mRNA activity were observed when control diets were supplemented with cholestyramine and mevinolin. When rats were fed these two drugs and then given mevalonolactone by stomach intubation, there was a 5-fold decrease of synthase mRNA within 3 h. These results indicate that cytoplasmic synthase regulation occurs primarily at the level of mRNA. This regulation is rapid and coordinate with that observed for HMG-CoA reductase. The chromosomal localization of human HMG-CoA synthase was determined by examining a panel of human-mouse somatic cell hybrids with the rat cDNA probe. Interestingly, the synthase gene resides on human chromosome 5, which has previously been shown to contain the gene for HMG-CoA reductase. Regional mapping, performed by examination of a series of chromosome 5 deletion mutants and by in situ hybridization to human chromosomes indicates that the two genes are not tightly clustered.

Amino Acid Sequence↗

PubMed1986

Bile acid-induced diarrhoea.

Three types of bile acid-induced diarrhoea can be distinguished. The best documented and most common entity is represented by type I bile acid malabsorption, which occurs as the result of a pathologically, anatomically defined ileopathy. Type II bile acid malabsorption is found in the setting of a morphologically completely normal ileum. This primary disorder of bile acid transport, which has been described in only a few paediatric and adult patients, appears to be rare. The third variety of bile acid malabsorption is characterized by the history of a previous cholecystectomy and/or by the presence of other gastroenterological conditions. Severe bile acid malabsorption is relatively uncommon in the type III syndrome. Even in the presence of severe bile acid malabsorption, patients with this condition are rarely found to have secretory concentrations of faecal bile acids, and/or rarely respond satisfactorily to cholestyramine. Present data suggest that bile acids play no significant role in the pathogenesis of idiopathic diarrhoea. A careful history, the measurement of stool weight and pH, a therapeutic trial of cholestyramine and the performance of a bile acid test, such as a bile acid breath test, can be used to establish the diagnosis of bile acid diarrhoea. Cholestyramine is the treatment of choice and is virtually always effective in this syndrome.

Bile Acids and Salts↗

PubMed1971

Effect of dietary tomatine on cholesterol metabolism in the rat.

Tomatine is a virtually nonabsorbable saponin which has been used as an antifungal agent and analytically as a cholesterol precipitant. It was used in this study to determine whether or not it can form a complex with cholesterol in vivo in the rat intestine and what effects such complex formation would have on cholesterol metabolism. Rats that were fed tomatine as 1% of the diet had a decreased uptake of dietary cholesterol by the liver, an increased rate of hepatic and intestinal cholesterol synthesis as well as a partial offsetting of the dietary cholesterol-induced decrease in hepatic cholesterogenesis, and an apparent increase in sterol excretion without an effect on bile acid excretion. In vitro, tomatine did not sequester cholic acid as did cholestyramine. The results show that tomatine has an effect on cholesterol absorption and on other aspects of lipid metabolism in the rat similar to that of cholestyramine, with the notable exception that tomatine increased sterol excretion while cholestyramine increased bile acid excretion. It was suggested that tomatine forms a nonabsorbable complex with cholesterol in the rat intestine.

Acetates↗

PubMed1981

Lipoprotein binding to canine hepatic membranes. Metabolically distinct apo-E and apo-B,E receptors.

Hepatic membranes from adult dog livers have receptors which bind to lipoproteins containing the E apoprotein (the apo-E HDLc) but lack specific receptors for the apo-B-containing low density lipoproteins (LDL). Scatchard analysis of direct binding data for 125I-apo-E-HDLc revealed nonlinearity of the binding which could be resolved into two components, suggesting the presence of two separate binding sites. The binding site for apo-E HDLc that possessed the highest affinity (Kd = 0.23 x 10(-9) M) was calcium-dependent and was sensitive to proteolytic digestion with pronase. The lower affinity (Kd = 20 x 10(-9) M) binding site for apo-E HDLc did not require calcium and was resistant to pronase digestion. Chemical modification of the arginyl or lysyl residues of the apo-E HDLc prevented the HDLc from binding to the higher affinity receptor but had no effect on their binding to the lower affinity site. Adult canine liver membranes also bound canine 125I-HDL. However, the binding of HDL was of lower affinity (Kd = 8.2 x 10(-8) M), did not require calcium, was not blocked by modification of the lysyl or arginyl residues, and may not be of physiologic significance. Although the liver membranes from normal chow-fed adult dogs did not bind canine LDL, it was possible to demonstrate specific high affinity binding of LDL under certain metabolic conditions in dogs. When adult dogs were treated with the hypocholesterolemic agent cholestyramine, the liver membranes from these animals readily bound canine LDL. The Kd for canine LDL binding to these liver membranes was 15 x 10(-9) M. Furthermore, it was possible to demonstrate high affinity binding of LDL to the liver membranes from young rapidly growing puppies (Kd = 11 x 10(-9) M). The binding of the 125I-LDL to the liver membranes from the adult cholestyramine-treated dogs or from the puppies appeared to be mediated by apo-B,E receptors which resembled the LDL receptor of human skin fibroblasts. The 125I-LDL binding of these liver membranes was competitively inhibited by the addition of unlabeled LDL or apo-E HDLc. On the other hand, 125I-apo-E HDLc, capable of binding to the apo-B,E or to the apo-E receptors, were only partially displaced by the addition of unlabeled LDL but were totally displaced by apo-E HDLc. In summary, the adult dog liver possessed only the apo-E receptor. An apo-B,E receptor capable of binding LDL and HDLc could be induced by treatment of adult dogs with cholestyramine. Similarly, the liver membranes of young growing puppies possessed the apo-E and po-B,E receptors and were capable of binding both apo-E HDLc and LDL. The mechanism responsible for the control of the expression of the hepatic apo-B,E and/or apo-E receptors remains to be determined. These data indicate that a unique receptor capable of interacting specifically with apo-E-containing lipoproteins, and not with apo-B-containing lipoproteins (LDL), exists in the adult canine liver.

Animals↗

PubMed1983

Bile acids and lipids in isolated rat hepatocytes. II. Source of cholesterol used for bile acid formation, estimated by incorporation of tritium from tritiated water, and by the effect of ML-236B.

After incubation in the presence of tritiated water, incorporation of tritium into cholesterol and into different bile acids was several-fold higher using hepatocytes of cholestyramine-fed rats than that found using hepatocytes of control rats. Labeling of the trihydroxylated cholic and beta-muricholic acids was markedly greater than that of dihydroxycholanoic acid. The total amount of label in all bile acids was 30% or less of that in free cholesterol, in both types of hepatocytes. In combination with the data on bile acids mass production we could calculate the average number (N(a)) of tritium atoms incorporated per molecule of newly-formed bile acid. The experimental values of N(a) for cholic and beta-muricholic acid were compared with values of N(n) or N(o), theoretically predicted if these bile acids were derived entirely from newly made or pre-existent cholesterol, respectively. It was deduced for hepatocytes of cholestyramine-fed rats that the bile acids produced in the first hour of incubation should be totally derived from pre-existent cholesterol, whereas 50% and 25% of the cholic and beta-muricholic acid, respectively, produced during the second and third hours of incubation should be derived from newly synthesized cholesterol. The contribution of newly made cholesterol as substrate for bile acid production was also estimated by using ML-236B. In a concentration of 12 micro M, it depressed cholesterol synthesis by 90% during 1 or 3 hours of incubation of hepatocytes of cholestyramine-fed rats. Mass production of cholic acid was depressed by 25% and that of beta-muricholic acid was not inhibited at all by ML-236B during the first hour of incubation, while they were depressed by 71 and 52%, respectively, during the second plus third hours of incubation. It is concluded that 1) in isolated hepatocytes newly made cholesterol can be a significant substrate for bile acid formation; 2) there are separate cholesterol substrate pools for the productions of cholic or beta-muricholic acid; 3) of the total carbon flux directed into cholesterol synthesis, the major part ends up as free cholesterol and only a minor part as bile acids, even in hepatocytes with a derepressed bile acid production.-Kempen, H. J., M. Vos-van Holstein, and J. de Lange. Bile acids and lipids in isolated rat hepatocytes. II. Source of cholesterol used for bile acid formation, estimated by incorporation of tritium from tritiated water, and by the effect of ML-236B.

Animals↗

PubMed1978

Partial "feedback control" of beta-hydroxy-beta-methylglutaryl coenzyme A reductase activity in primary hepatocellular carcinomas.

The activity of beta-hydroxy-beta-methylglutaryl coenzyme A reductase, the rate-controlling enzyme of cholesterol synthesis, was studied in normal livers and in 64 primary hepatocellular carcinomas from rats fed a basal diet or a diet containing either 2% cholestyramine or 5% cholesterol. The average enzyme activity in hepatocellular carcinomas from rats fed the basal diet was more than twice that in normal liver. Dietary cholesterol caused a reduction in activity to one-ninth of the normal hepatic enzyme activity, whereas cholestyramine feeding resulted in a 7-fold increase above the basal level. The data tended to confirm the previously documented observation that "diet-induced feedback inhibition" of cholesterol synthesis is not expressed in hepatomas, since the enzyme activity was reduced only slightly in cancers from rats fed cholesterol. However, the activities from cancers of cholestyramine-fed rats were 2.7 times greater than those from cholesterol-fed rats. Thus, a degree of control was clearly demonstrable, although it represented only 4% of that seen in normal liver. To our knowledge this is the first report of at least partial "feedback control" of beta-hydroxy-beta-methylglutaryl coenzyme A reductase activity in hepatocellular carcinomas grown in vivo.

Animals↗

PubMed1994

[Drug treatment of hyperlipoproteinemia: bile acid-binding resins].

Bile acid-binding resins, one of which is cholestyramine that has long been used in Japan, are extremely safe and effective hypocholesterolemic agents. The agents block an enterohepatic circulation of bile acids leading to an enhancement of bile acid synthesis, which may lead to decrease in hepatic levels of cholesterol. This will induce the liver to upregulate the LDL receptor activity causing a reduction of serum LDL cholesterol levels. One of the major problems of cholestyramine is a poor drug compliance. MCI-196, a newly developed bile acid resin, is more potent than cholestyramine and will be expected to improve this problem.

Anticholesteremic Agents↗

PubMed1994

Effects of different bile salts on steady-state mRNA levels and transcriptional activity of cholesterol 7 alpha-hydroxylase.

Cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in the bile acid synthesis pathway, is down-regulated by taurocholate by way of negative feedback control at the level of gene transcription. The molecular basis of regulation of cholesterol 7 alpha-hydroxylase by other hydrophobic bile salts and under more physiological conditions is not known. The aim of this study was to investigate the molecular basis of regulation of cholesterol 7 alpha-hydroxylase by several naturally occurring bile salts in rats with intact enterohepatic circulation. Male Sprague-Dawley rats were pair-fed for 14 days normal chow (control), cholestyramine (5% of diet), cholic acid (1%), chenodeoxycholic acid (1%) or deoxycholic acid (0.25%). When rats were killed, livers were harvested and HMG-CoA reductase specific activity and cholesterol 7 alpha-hydroxylase specific activities, steady-state mRNA levels and transcriptional activity were determined and compared with those of control rats fed normal chow. Compared with results in paired controls, cholestyramine feeding led to an approximate threefold increase in HMG-CoA reductase specific activity. Feeding of hydrophobic bile salts profoundly decreased the specific activity of HMG-CoA reductase. Cholestyramine led to a three-fold increase in cholesterol 7 alpha-hydroxylase specific activity, steady-state mRNA levels and gene transcriptional activity. The feeding of cholic (1%), chenodeoxycholic (1%) and deoxycholic acid (0.25%) led to significant decreases in cholesterol 7 alpha-hydroxylase specific activities (62%, 84% and 97%, respectively), steady-state mRNA levels (72%, 29% and 61%, respectively) and transcriptional activities (44%, 43% and 54%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animal Feed↗

PubMed1993

Collagenous colitis: are bacterial cytotoxins responsible?

In a case of collagenous colitis, cholestyramine treatment resulted in symptomatic and histological normalization. After discontinuation of cholestyramine, collagenous colitis relapsed. At this time fecal cytotoxic activity was demonstrated in McCoy cell lines. Symptoms, histologic changes, and cytotoxicity disappeared when cholestyramine treatment was reinstituted. We hypothesize that a bacterial toxin is responsible for the development of collagenous colitis.

Aged↗

PubMed1995

Idiopathic bile acid malabsorption: long-term outcome.

OBJECTIVE: Idiopathic bile acid malabsorption (IBAM) is a rare cause of diarrhoea. The natural history of this disorder has not previously been reported. The aim of our study was to determine the long-term outcome in a cohort of patients with severe IBAM using a subjective assessment and by measuring the proportion of 75Se-homocholic acid taurine (75SeHCAT) retained 7 days after its ingestion. PATIENTS AND METHODS: Twenty-three patients with IBAM were identified in 1989. All had responded well to treatment with a bile acid chelator (cholestyramine or aluminium hydroxide). Questionnaires relating to current clinical symptoms and prescriptions were sent to these patients and their general practitioners. 75SeHCAT tests were performed for objective assessment. RESULTS: Three patients were lost to follow-up, three had died owing to malignancy and three had been diagnosed as suffering from inflammatory bowel disease. The mean period of follow-up for the remaining fourteen patients was 99.2 (range 48-140) months. Seven of the patients showed an improvement in symptoms and no longer required treatment with cholestyramine. In the remaining seven symptomatic patients, diarrhoea was well controlled by continued treatment with cholestyramine (five patients) or standard anti-diarrhoeal treatment (two patients). All seven symptomatic patients and three asymptomatic patients underwent repeat 7 day 75SeHCAT tests. The test results in the asymptomatic group had all improved so that the retention of the tracer after 7 days was above 5%; all but two patients in the symptomatic group still had values under 5%. However, the small number of patients in both groups precluded statistical analysis. CONCLUSIONS: IBAM is a rare cause of diarrhoea and should be diagnosed only after malignancy and inflammatory bowel disease have been excluded by rigorous investigations. Patients should be followed up as some develop other serious gastrointestinal diseases. Fifty per cent of the patients in our survey have remitted spontaneously and no longer require medication with bile acid chelators or anti-diarrhoeal agents.

Antidiarrheals↗

PubMed1987

Dietary acetate and cholesterol metabolism in rats.

Rats were fed either cholesterol-free or high-cholesterol (1%, w/w) semipurified diets containing acetate (0.5%) or cholestyramine (0.44%) or both compounds for 29 days. The bile-acid binding resin, cholestyramine, did not affect serum and liver cholesterol, irrespective of whether the diet was cholesterol-free or contained cholesterol. In the cholesterol-free diets, acetate tended to lower the concentration of serum cholesterol, but did not influence liver cholesterol. When the diets contained cholesterol, acetate lowered liver cholesterol concentrations by about 20% both in the presence and absence of cholestyramine. Acetate did not affect the excretion of bile acids in feces. The mechanism by which acetate may partly counteract the increase in liver cholesterol seen after cholesterol feeding of rats, remains to be established.

Acetates↗

PubMed1984

Cholesterol binding capacity of fiber from tropical fruits and vegetables.

The cholesterol binding capacity of 28 fiber samples from a variety of the more common tropical fruits and vegetables was determined. The binding capacity of cholestyramine, cellulose, lignin, guar gum and citrus pectin were also determined. Capacities were evaluated by an in vitro method that simulates the effect of the human digestive system on fiber using a series of enzymatic treatments before the binding was determined. Binding values varied from 3% for a soluble fraction of cassava to 84% for cholestyramine. Values for most fruit and vegetable fiber samples were less than or ca. equal to cellulose or lignin (20% and 16%, respectively). Apart from cholestyramine, sweet potato was the most effective binder (30%). Citrus pectin, at 8%, was a relatively poor binder. The capacity of guar gum (17%) was slightly less than cellulose. These data do not support the conclusion from in vivo studies that the hypocholesteremic effects observed for citrus pectin and guar gum are the result of the direct binding of cholesterol or bile acids in the large intestine.

Cellulose↗

PubMed1990

Increase in selective hepatic uptake of high-density lipoprotein cholesteryl esters in the fasted rabbit.

The selective hepatic uptake of high-density lipoprotein cholesteryl esters was determined in primary hepatocyte cultures of cells from normal, cholestyramine-fed and 48-h-fasted rabbits. The HDL was labeled in the apoprotein moiety with [14C]sucrose and in the core component with [3H]cholesteryl linoleyl ether. The uptake of the apoprotein label did not differ between groups (indicating no change in holoparticle HDL uptake), but in contrast, the uptake of the cholesteryl ether label was significantly increased in hepatocytes from cholestyramine-fed and fasted animals. After 40 h of culture, the ratio of 3H to 14C uptake was 4.96 in controls cells, 7.15 in cholestyramine-treated cells and 10.24 in fasted hepatocytes from short-term fasted animals. Thus short-term fasting was associated with a 2-fold increase in the selective hepatic uptake of HDL core components, indicating that selective hepatic uptake of HDL cholesteryl esters is a physiologically responsive process.

Animals↗

PubMed2002

Effects of bile salt flux variations on the expression of hepatic bile salt transporters in vivo in mice.

BACKGROUND/AIMS: Expression of hepatic bile salt transporters is partly regulated by bile salts via activation of nuclear farnesoid X-activated receptor (Fxr). We investigated the physiological relevance of this regulation by evaluating transporter expression in mice experiencing different transhepatic bile salt fluxes. METHODS: Bile salt flux was manipulated by dietary supplementation with taurocholate (0.5% w/w) or cholestyramine (2% w/w) or by disruption of the cholesterol 7alpha-hydroxylase-gene (Cyp7A(-/-) mice) leading to reduced bile salt pool size. Expression of hepatic transporters was assessed (polymerase chain reaction (PCR), immunoblotting, and immunohistochemistry). RESULTS: Biliary bile salt secretion was increased (+350%) or decreased (-50%) after taurocholate or cholestyramine feeding, respectively, but plasma bile salt concentrations and hepatic Fxr expression were not affected. The bile salt uptake system Na(+)-taurocholate co-transporting polypeptide (Ntcp) and organic anion transporting polypeptide-1 (Oatp1) were down-regulated by taurocholate and not affected by cholestyramine feeding. Cyp7A(-/-) mice did not show altered Ntcp or Oatp1 expression. Canalicular bile salt export pump (Bsep) was up-regulated by 65% in taurocholate-fed mice, and slightly down-regulated in Cyp7A(-/-) mice. CONCLUSIONS: Large variations in hepatic bile salt flux have minor effects on expression of murine Ntcp and Bsep in vivo, suggesting that these transporters are abundantly expressed and able to accommodate a wide range of 'physiological' bile salt fluxes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1988

Dietary fiber and intestinal adaptation: effects on lipid absorption and lymphatic transport in the rat.

Adult male rats fed defined diets containing various fiber supplements or cholestyramine for 4 wk were surgically provided with lymphatic drainage catheters and starved overnight. After duodenal administration of a standard lipid test emulsion, absorption rates and lipoprotein distributions of cholesterol and oleic acid were determined. Prefeeding diets containing cellulose or alfalfa had no significant effect on oleic acid absorption. Diets containing pectin, guar gum, metamucil, mixed fibers (Fibyrax), or cholestyramine caused decreased lymphatic recovery in the initial period; except for the metamucil diet, no decrease was caused in the 24-h recovery, suggesting delayed but not impaired absorption. Fatty acid distribution among lipoproteins and chylomicron size were not altered by diet. All supplements caused a significant reduction in cholesterol absorption during the initial period, and cholesterol absorption remained depressed in animals prefed pectin, guar gum, mixed fibers, metamucil, and cholestyramine.

Animals↗

PubMed1989

New horizons in combination drug therapy for hypercholesterolemia.

A modest number of hypolipidemic drugs are currently available, and their use as single agents frequently fails to adequately control patients with severe hypercholesterolemia. Combined-drug regimens afford the opportunity to maximize the cholesterol-lowering effects of drugs that have different mechanisms of action and, at the same time, minimize potential side effects. The bile acid sequestrants (cholestyramine and colestipol) enhance fecal sterol excretion and are nonsystemically acting; they have provided the cornerstone for the majority of the established combined-drug regimens. The most effective regimens have used bile acid sequestrants in combination with nicotinic acid, or more recently, lovastatin or simvastatin. Combinations in which fenofibrate, bezafibrate, or probucol have been used with cholestyramine or colestipol have also been shown to be useful although the low-density-lipoprotein-lowering effect of probucol appears quite variable. The use of low doses of bile acid sequestrants (4-8 g/day of cholestyramine or 5-10 g/day of colestipol) in combination with lovastatin, simvastatin, or probucol provides a therapeutic regimen that is usually well tolerated, shows additive lipid lowering, and is cost effective.

Anticholesteremic Agents↗

PubMed1981

Atherosclerosis in the tongue of the rhesus monkey.

Atherosclerotic vascular lesions in rhesus monkey tongues were studied, in both induction and regression periods. Vascular lesions were induced by peanut oil and a combination of coconut oil and butter fat, which caused the rapid elevation of serum lipids of all the animals. Atherosclerotic lesions were found in the tongues of all animals on an atherogenic diet. Larger arteries were found to be more susceptible to the disease. During the regression period animals received either a low-fat, low-cholesterol diet with or without cholestyramine, or an atherogenic diet with cholestyramine. Regression of the disease was more significant in animals on a low-fat, low-cholesterol and cholestyramine diet. Lesions in larger arteries in the tongues appeared to respond to the treatment more rapidly.

Animals↗