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PubMed2007

Prevention and treatment of obesity, insulin resistance, and diabetes by bile acid-binding resin.

Bile acid-binding resins, such as cholestyramine and colestimide, have been clinically used as cholesterol-lowering agents. These agents bind bile acids in the intestine and reduce enterohepatic circulation of bile acids, leading to accelerated conversion of cholesterol to bile acids. A significant improvement in glycemic control was reported in patients with type 2 diabetes whose hyperlipidemia was treated with bile acid-binding resins. To confirm the effect of such drugs on glucose metabolism and to investigate the underlying mechanisms, an animal model of type 2 diabetes was given a high-fat diet with and without colestimide. Diet-induced obesity and fatty liver were markedly ameliorated by colestimide without decreasing the food intake. Hyperglycemia, insulin resistance, and insulin response to glucose, as well as dyslipidemia, were markedly and significantly ameliorated by the treatment. Gene expression of the liver indicated reduced expression of small heterodimer partner, a pleiotropic regulator of diverse metabolic pathways, as well as genes for both fatty acid synthesis and gluconeogenesis, by treatment with colestimide. This study provides a molecular basis for a link between bile acids and glucose metabolism and suggests the bile acid metabolism pathway as a novel therapeutic target for the treatment of obesity, insulin resistance, and type 2 diabetes.

Adipose Tissue↗

PubMed1985

Idiopathic bile acid diarrhoea reconsidered.

Two new cases of a rare entity provisionally coined 'idiopathic bile acid diarrhoea' are reported and compared with previous cases. The diarrhoeal syndrome has been identified as a cholegenic enteropathy. In the absence of conventional ileopathy the cause of the bile acid loss is obscure, but it is hypothesized that it may be due to a relative deficiency in ileal absorptive sites for bile acid anions. So far the diagnosis has partly been based on measurements of faecal bile acid losses. It is suggested that a carefully conducted therapeutic trial with cholestyramine may be almost equally helpful.

Aged↗

PubMed1991

Regulation of hepatic cholesterol metabolism in man.

The liver is a key element in regulating the amount of low density lipoprotein (LDL) cholesterol in plasma. The interference of cholestyramine treatment in the enterohepatic circulation of bile acids stimulates the activity of the rate limiting enzymatic step in bile acid biosynthesis (cholesterol 7 alpha-hydroxylase). This increases demand for cholesterol which is met by enhanced cholesterol biosynthesis (through the enzyme 3-hydroxy-3-methylglutaryl coenzyme A [HMG CoA] reductase) and by an increased expression of LDL receptors. Inhibition of HMG CoA reductase activity by treatment with specific inhibitors such as pravastatin enhances LDL receptor binding activity. Combination of the two treatments results in a significant stimulation of LDL receptor expression and a drastic reduction in the concentration of plasma LDL cholesterol. Thus, selective interference with bile acid enterohepatic circulation and cholesterol biosynthesis may be utilised to regulate plasma lipoprotein metabolism.

Cholelithiasis↗

PubMed1990

Adsorption of bilirubin with polypeptide-coated resins.

Poly-L-lysine, poly-D-lysine and poly-L-ornithine have been coated covalently onto a water-swellable polyamide resin. These sorbents, especially the polylysine coated resins, exhibit high binding affinities for bilirubin in aqueous phosphate buffer solutions at 0 degrees C. The polylysine coated resins have an improved binding affinity for bilirubin over the sorbents with lysine containing oligopeptide pendants and much higher affinity than cholestyramine. The binding capacity is directly proportional to the number of lysine residues on the resin. Replacement of poly-L-lysine with poly-D-lysine does not affect the adsorption capacity.

Absorption↗

PubMedDate not supplied

Subacute chlordane poisoning.

A 30 year old female was exposed to chlordane through careless and excessive domestic use over a 1 to 4 week period. Early symptoms included circumoral numbness, anorexia, nausea, and fatigue. Myoclonic jerks occurred after a delay of one month. Malaise and anorexia became the dominant symptoms leading to referral at six months. Dysfunctional bleeding was attributed to hepatic enzyme induction by the chlordane and increased metabolism of contraceptive medication. Cholestyramine increased the stool elimination of chlordane.

Adipose Tissue↗

PubMed1992

Ontogeny of taurocholate accumulation in the terminal ileal mucosal cells of young chicks.

The everted, ileal ring technique of Little and Lester was utilized to study taurocholate accumulation against a concentration gradient in the terminal ileal mucosal cells of chicks from hatch to 6 wk of age. The chicks had low levels of taurocholate accumulation at hatch. A three- to fourfold increase in accumulation was observed at Day 3 posthatch, but taurocholate returned to baseline levels within 2 days. This peak has not been previously reported in any other species. The age-related peak in the ileal accumulation of taurocholate was not influenced by removal of the yolk sac at hatch, oral feeding of yolk, or supplementation of the diet with taurocholate or cholestyramine. Comparison of ileal uptake of proline versus uptake of taurocholate during the 1st wk posthatch indicated that the peak in ileal taurocholate accumulation is not the result of a general increase in absorptive capacity through cell proliferation. These data suggest that the age-related changes in taurocholate absorption are genetically determined and are not responsive to external influences.

Aging↗

PubMed2004

Differential expression of cholangiocyte and ileal bile acid transporters following bile acid supplementation and depletion.

AIM: We have previously demonstrated that cholangiocytes, the epithelial cells lining intrahepatic bile ducts, encode two functional bile acid transporters via alternative splicing of a single gene to facilitate bile acid vectorial transport. Cholangiocytes possess ASBT, an apical sodium-dependent bile acid transporter to take up bile acids, and t-ASBT, a basolateral alternatively spliced and truncated form of ASBT to efflux bile acids. Though hepatocyte and ileal bile acid transporters are in part regulated by the flux of bile acids, the effect of alterations in bile acid flux on the expression of t-ASBT in terminal ileocytes remains unclear. Thus, we tested the hypothesis that expression of ASBT and t-ASBT in cholangiocytes and ileocytes was regulated by bile acid flux. METHODS: Expression of ASBT and t-ASBT message and protein in cholangiocytes and ileocytes isolated from pair-fed rats given control (C) and 1% taurocholate (TCA) or 5% cholestyramine (CY) enriched diets, were assessed by both quantitative RNase protection assays and quantitative immunoblotting. The data obtained from each of the control groups were pooled to reflect the changes observed following TCA and CY treatments with respect to the control diets. Cholangiocyte taurocholate uptake was determined using a novel microperfusion technique on intrahepatic bile duct units (IBDUs) derived from C, TCA and CY fed rats. RESULTS: In cholangiocytes, both ASBT and t-ASBT message RNA and protein were significantly decreased in response to TCA feeding compared to C diet. In contrast, message and protein of both bile acid transporters significantly increased following CY feeding compared to C diet. In the ileum, TCA feeding significantly up-regulated both ASBT and t-ASBT message and protein compared to C diet, while CY feeding significantly down-regulated message and protein of both bile acid transporters compared to C diet. As anticipated from alterations in cholangiocyte ASBT expression, the uptake of taurocholate in microperfused IBDUs derived from rats on TCA diet decreased 2.7-fold, whereas it increased 1.7-fold in those on CY diet compared to C diet fed groups. CONCLUSION: These data demonstrate that expression of ASBT and t-ASBT in cholangiocytes is regulated by a negative feedback loop while the expression of these transporters in terminal ileum is modified via positive feedback. Thus, while transcriptional regulatory mechanisms in response to alterations in bile acid pool size are operative in both cholangiocytes and ileocytes, each cell type responds differently to bile acid supplementation and depletion.

Alternative Splicing↗

PubMed1978

Consequences of ileal dysfunction: an approach to management.

Fourteen patients with ileal dysfunction due to resection or bypass were encountered over an 18-month period. Symptoms had been present for a mean period of 1.8 years. Diarrhoea was a universal symptom, and varied from mild to incapacitating. Weight loss, due in part to malabsorption and in part to the patients' fear of eating, occurred in 10 of 14 patients. The chief metabolic abnormalities were steatorrhoea and hypokalaemia. Vitamin B12 deficiency, folate deficiency, anaemia, hypoalbuminaemia, hypocalcaemia, hypomagnesaemia, hyperoxaluria, and an abnormal prothrombin ratio were less frequently seen. Treatment with cholestyramine and/or long-chain fat restriction effectively reduced diarrhoea in every case, and this was supplemented by replacement of specific deficiencies. There was little added benefit from non-specific antidiarrhoeal agents. It was found that the major symptoms of ileal dysfunction are readily treated, but that attention should also be given to a number of nutritional deficiencies.

Adult↗

PubMed1985

Postoperative reflux gastritis: pathophysiology and long-term outcome after Roux-en-Y diversion.

Sixteen patients with clinical features of postoperative gastritis who had been advised to have a Roux-en-Y diversion were studied prospectively. Studies were done pre- and postoperatively (mean follow-up, 4.9 years; range, 3.8 to 6.9), and the findings were compared with those in 11 control subjects with previous enterogastric anastomosis but with no symptoms. The patients had higher concentrations of bile acids and trypsin in gastric samples than did controls. Patients had greater endoscopic changes, although mucosal histologic characteristics were similar in both groups. Administration of aluminum hydroxide or cholestyramine reduced the aqueous concentrations of bile acids in gastric contents. Roux-en-Y diversion virtually eliminated duodenogastric reflux, and gastroscopic appearances returned to normal. However, Roux-en-Y diversion did not change mucosal histologic characteristics. Symptom scores were reduced in the early postoperative period, but bilious vomiting was the only symptom alleviated consistently and permanently. As a treatment for postoperative gastritis, Roux-en-Y diversion offers potential but limited benefits.

Adult↗

PubMed2005

A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events.

BACKGROUND: The high-density lipoprotein (HDL) cholesterol level is a strong predictor of cardiovascular events in epidemiologic studies. Until recently, it has been less extensively studied as a therapeutic target. OBJECTIVE: To assess the angiographic and clinical effects of a pharmacologic strategy to increase HDL cholesterol levels. DESIGN: Randomized, double-blind, placebo-controlled trial conducted from 1993 to 1996. SETTING: Outpatient specialty clinic of a large U.S. military medical center. PARTICIPANTS: 143 military retirees younger than 76 years of age with low HDL cholesterol levels and angiographically evident coronary disease. INTERVENTION: Gemfibrozil, niacin, and cholestyramine or corresponding placebos, with aggressive dietary and lifestyle intervention at baseline. MEASUREMENTS: Change from baseline to 30 months and a composite measure of clinical events that included hospitalization for angina, myocardial infarction, transient ischemic attack and stroke, death, and cardiovascular procedures. RESULTS: At baseline, mean (+/-SD) lipid values were as follows: total cholesterol, 5.1 +/- 0.8 mmol/L (196 +/- 31 mg/dL); low-density lipoprotein (LDL) cholesterol, 3.3 +/- 0.7 mmol/L (128 +/- 27 mg/dL); and HDL cholesterol, 0.9 +/- 0.2 mmol/L (34 +/- 6 mg/dL). Compared with placebo, the pharmacologically treated group experienced a 20% (95% CI, 14.8% to 24.3%) decrease in total cholesterol level, a 36% (CI, 28.4% to 43.5%) increase in HDL cholesterol level, a 26% (CI, 19.1% to 33.7%) decrease in LDL cholesterol level, and a 50% (CI, 40.5% to 59.2%) reduction in triglyceride levels. Focal coronary stenosis increased by 1.4% in the placebo group but decreased by 0.8% in the drug group (difference, -2.2 percentage points [CI, -4.2 to -0.1 percentage points]). A composite cardiovascular event end point was reached in 26% of patients in the placebo group and 13% of those in the drug group (difference, 13.7 percentage points [CI, 0.9 to 26.5 percentage points]). Side effects, particularly flushing and gastrointestinal intolerance, were more common in the drug group but rarely led to withdrawal from the study. LIMITATIONS: The study was small and used a composite clinical outcome. Whether improvements in angiographic findings were due to reductions in LDL cholesterol or increases in HDL cholesterol was not established. Flushing may have led to inadvertent unblinding in patients who were randomly assigned to active study drugs. CONCLUSIONS: A combination regimen aimed at increasing HDL cholesterol levels improves cholesterol profiles, helps prevent angiographic progression of coronary stenosis, and may prevent cardiovascular events in some people who exercise regularly and eat low-fat diets.

Aged↗

PubMed1976

The common hyperlipoproteinemias: an understanding of disease mechanisms and their control.

Our review focuses on low density lipoprotein (LD lipoprotein) and very low density lipoprotein (VLD lipoprotein) in their roles as transporters of cholesterol and triglyceride and as factors contributing to premature arteriovascular disease. We describe the clinical manifestations of the common, primary hyperlipoproteinemias--that is, hyper-beta-lipoproteinemia, combined hyperlipoproteinemia, hyper-pre-beta-lipoproteinemia, and sporadic hyperlipoproteinemia--and discuss the variations in lipoprotein structure and metabolism that occur in these diseases. Based on an understanding of the physiologic control of lipoprotein metabolism, it is possible for the physician to alter the concentrations of LD lipoprotein and VLD lipoprotein by selecting a course of therapy appropriate to the specific disease. We describe the effects of obesity, diet, insulin, ethanol, estrogens, and the drugs clofibrate, nicotinic acid, and cholestyramine.

Cholestyramine Resin↗

PubMed1978

[Therapeutic problems in the "short-bowel-syndrome" (author's transl)].

The authors report on 6 children with short-bowel-syndrome. The expectancy of life of the patients depends on the mucosal surface of the residual intestine and on the degree of adaption. After removal of larger proportions of the intestine, nutrition should be started parenterally and followed by an early but cautious oral feeding. The administration must be distributed continuously over the day. At first carbohydrates are given as monosaccharides, fats as M. C. T. and proteins as amino acid mixtures. Carrot soup has proved useful as a water-binding substance for the improvement of stool consistency. An anabolic condition of the metabolism should be maintained. Therapy with cholestyramin is indicated in chologenic diarrhoea. Substitution of vitamins, especially vitamin B12 is very important after resection of the ileum.

Amino Acids↗

PubMed1976

[Importance of bile for stress ulcer in the rat].

The influence of bile on ulcer formation under restraint stress condition was studied in rats. Animals with a choledochogastrostomy or a pyloroplasty showed as many ulcers as the sham-operated controls. After choledochoileostomy or bile duct ligation the ulcer frequency was reduced by half. A pharmacologic binding of the bile salts by intragastral cholestyramine had the same effect.

Animals↗

PubMed1975

[Significance of pruritus during pregnancy. Relations with the hepatic disorders of gestation].

The principal clinical and biological characteristics and the origin of pruritus of pregnancy (p.p.) which occurs in a little more than two pregnancies per thousand are considered in the light of 7 cases. As with recurrent jaundice of pregnancy (r.j.p.), of which pruritus represents a minor analogue, the symptoms occur solely during pregnancy and disappear after delivery. In p.p. signs of cholestasis are seen, more marked than in a normal pregnancy coming to term but less than in icterus gravidarum. The increase in transaminases seen in p.p. and r.j.p. does not occur in normal pregnancy. The two conditions, which may be grouped together under the term hepatogestosis, are benign as far as the mother is concerned but represent a definite and significant risk of prematurity for the child. It is possible to establish a relation between p.p. and/or r.j.p. and the hepatic manifestations associated with oral contraceptives. In both instances a genetic predisposition seems to favour the development of a cholestatic syndrome. A past history of p.p. represents a contraindication to the use of oral contraceptives. Cholestyramine, a bile salt chelator, gives excellent results in persistent p.p.

Adult↗

PubMed1975

Cholesterol catabolism in the rabbit in fasted and fed states.

Urinary and fecal endogenous steroid excretion of fed or fasted New Zealand white rabbits was determined by the isotopic steady state method after subcutaneous implantation of radioactive cholesterol. While plasma cholesterol was increasing during a 9-day fast, fecal steroid excretion decreased to 10% of the excretion rates in the fed state. Refeeding the fasted rabbits led to a decrease in plasma cholesterol and an increase in fecal endogenous steroid excretion. Urinary steroid excretion, which represented 18% of total endogenous steroid excretion for fed animals, decreased during fasting and increased during refeeding, but these changes were relatively small. The small intestine, cecum, and colon of fed or fasted rabbits had similar endogenous steroid was acidic steroid. During attempts to alter the circulating bile acid concentration by supplying deoxycholate (200 mg/day) to fed rabbits or cholestyramine (2 g/day) to fasted rabbits, plasma cholesterol concentration did not change to the same extent as during fasting or refeeding, respectively. The decreased cholesterol catabolism and the hypercholesterolemia that are seen in the fasting rabbit may result from decreased clearance of plasma cholesterol.

Animals↗

PubMed1999

Cholesterol-lowering drugs. Some drugs with demonstrated efficacy but different benefits in primary and secondary prevention.

(1) In primary prevention trials, pravastatin and lovastatin prevented myocardial infarction and had a positive risk-benefit ratio in men with LDL-cholesterol values exceeding 4.5 mmol/l (1.7 g/l). Cholestyramine and gemfibrozil also prevented myocardial infarction in men with more severe hypercholesterolaemia; while clofibrate had a negative risk-benefit ratio in patients with moderate hypercholesterolaemia. These treatments have not been assessed for primary prevention in women or in patients aged over 70. (2) In trials involving patients with coronary heart disease, pravastatin and simvastatin both reduced the risk of myocardial infarction and/or mortality in patients of both sexes with LDL-cholesterol values above 3.2 mmol/l (1.2 g/l). Gemfibrozil also reduced the risk of myocardial infarction but not mortality, while clofibrate and bezafibrate had no preventive effect.

Anticholesteremic Agents↗

PubMed1979

Studies on some possible biochemical treatments of primary hyperoxaluria.

The effects of some putative inhibitors of oxalate production or urinary oxalate excretion have been investigated in the Cynamolgus monkey and in patients with Type I primary hyperoxaluria (hyperoxaluria with glycollic aciduria). Sodium-1-hydroxybutan-sulphonate, D,L-phenyllactate, succinimide and isocarboxazide did not reduce the urinary oxalate excretion in the monkeys. Pyridoxine reduced the excretion of oxalate and glycollate in some patients, and its therapeutic use has been documented over a five-year period. Succinimide, which has been used by other workers for the treatment of non-hyperoxaluric stone formers, did not decrease the excretion of either oxalate or glycollate in three patients in whom it was tried. It did not change the inhibitory activity of the urine with respect to the growth and aggregation of calcium oxalate crystals in any of the three patients, and it did not have any consistent effect on the excretion of calcium oxalate crystals in the one patient who had detectable crystaluria before treatment. We have identified several metabolites of succinimide in the urine of patients taking the drug. These include 2,3-dehydrosuccinamic, 2-hydroxysuccinamic and 3-hydroxysuccinamic acids. Isocarboxazide, cholestyramine and thiamine did not affect the urinary oxalate excretion in the patients. The significance of these observations from the viewpoint of the treatment of primary hyperoxaluria is discussed.

Adolescent↗

PubMed2001

Measurement of parameters of cholic acid kinetics in plasma using a microscale stable isotope dilution technique: application to rodents and humans.

A stable isotope dilution method is described that allows measurement of cholic acid (CA) kinetics, that is, pool size, fractional turnover rate (FTR), and synthesis rate in mice, rats, and humans. Decay of administered [2,2,4,4-2H4]CA enrichment was measured in time in 50-microl plasma samples by gas-liquid chromatography/electron capture negative chemical ionization-mass spectrometry, applying the pentafluorobenzyl-trimethylsilyl derivative. The kinetic data expressed species-dependent differences. The CA pool sizes were 16.8 +/- 2.1, 10.6 +/- 1.2, and 2.4 +/- 0.7 micromol/100 g body weight for mice, rats, and humans, respectively. The FTR values were 0.44 +/- 0.03, 0.88 +/- 0.10, and 0.46 +/- 0.14 per day for mice, rats, and humans. The corresponding synthesis rates were 7.3 +/- 1.6, 9.3 +/- 0.1, and 1.0 +/- 0.2 micromol/100 g body weight per day. The human data agreed well with literature data obtained by conventional isotope dilution techniques. For rats and mice these are the first reported isotope dilution data. The method was validated by confirmation of isotopic equilibrium between biliary CA and plasma CA in the rat. Its applicability was demonstrated by the observation of increased CA FTR and CA synthesis rate in rats fed cholestyramine, which is known to increase fecal bile acid excretion. The presented stable isotope dilution method enables the determination of CA kinetic parameters in small plasma samples. The method can be applied in unanesthetized rodents with an intact enterohepatic circulation and may also be valuable when studying the development of human neonatal bile acid kinetics.

Adult↗