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Folkert Kuipers - One of the best experts on this subject based on the ideXlab platform.

  • Bile Acid Sequestrants and the Treatment of Type 2 Diabetes Mellitus
    Drugs, 2007
    Co-Authors: Bart Staels, Folkert Kuipers
    Abstract:

    Bile acids promote bile formation and facilitate dietary lipid absorption. Animal and human studies showing disturbed bile acid metabolism in diabetes mellitus suggest a link between bile acids and glucose control. Bile acids are activating ligands of the farnesoid X receptor (FXR), a nuclear receptor with an established role in bile acid and lipid metabolism. Evidence suggests a role for FXR also in maintenance of glucose homeostasis. Animal and human studies employing bile acid sequestrants (bile acid binding agents), which interrupt the enterohepatic circulation of bile acids and effectively reduce plasma cholesterol, support a link between bile acid and glucose metabolism. In lipid-lowering trials, bile acid sequestrants, such as colesevelam hydrochloride, colestyramine (Cholestyramine) and colestilan (colestimide), have also been shown to lower plasma glucose and glycosylated haemoglobin levels, suggesting the utility of these agents as a potential therapy for type 2 diabetes. In this article, we review the relationship between bile acid metabolism and glucose homeostasis, and present data demonstrating the utility of bile acid sequestrants in the management of diabetes.

Shinichiro Yokoyama - One of the best experts on this subject based on the ideXlab platform.

  • gene expression analysis on the liver of Cholestyramine treated type 2 diabetic model mice
    Biomedicine & Pharmacotherapy, 2010
    Co-Authors: Kenji Matsumoto, Shinichiro Yokoyama
    Abstract:

    Recent experimental and clinical studies have indicated that bile acid-binding agents are effective not only for treating hypercholesterolemia, but also for type 2 diabetes. To investigate the molecular mechanism underlying the effect of Cholestyramine, a bile acid-binding agent, on type 2 diabetes, we examined gene expression of the livers of Cholestyramine-treated type 2 diabetic model mice. Type 2 diabetic NSY/Hos mice were fed a high fat diet supplemented with 1% (w/w) Cholestyramine for 8 weeks. Cholestyramine treatment prevented the increase in body weight, plasma cholesterol, triglycerides, glucose, insulin levels, and hepatic steatosis. DNA microarray analysis was performed on the liver, which revealed that the genes related to synthesis of cholesterol and its derivatives were increased and the genes regulated by liver X receptors, such as the sterol regulatory element-binding protein 1 gene, were decreased in the group treated with Cholestyramine. Expression of the genes related to carbohydrate metabolism was little changed in the Cholestyramine group. Furthermore, we performed real-time RT-PCR analysis, which highly correlated with DNA microarray data (r=0.957, P<0.001). This study provides a valuable basis for further research on the biological functions of bile acid-binding agents in models of type 2 diabetes.

Shlomo Eisenberg - One of the best experts on this subject based on the ideXlab platform.

  • Effects of Cholestyramine on lipoprotein levels and metabolism in Syrian hamsters.
    Biochimica et biophysica acta, 1992
    Co-Authors: Pieter H. E. Groot, Nigel J. Pearce, Keith E. Suckling, Shlomo Eisenberg
    Abstract:

    Abstract Oral administration of Cholestyramine to adult male hamsters not only induced a marked decrease in plasma concentrations of cholesterol and LDL but had a similar lowering effect on plasma triacylglycerol and VLDL concentrations. The hypotriglyceridaemic effects of resin administration were not due to an increase in lipoprotein lipase, as post-heparin plasma lipoprotein lipase activities were unchanged, but rather to a 35% decrease in VLDL synthesis. Measurement of the disappearance rate of apolipoprotein B from VLDL after i.v. injection of 125I-labelled hamster or human VLDL into control and Cholestyramine-fed recipient animals showed a 2-times lower T 1 2 in the drug-treated animals. The fraction of VLDL apolipoprotein B, recovered at any time after injection in the LDL, was equal or higher in Cholestyramine-fed animals as compared to controls. These data indicate that the lowering in plasma LDL by Cholestyramine in male hamsters is due not only to LDL receptor up-regulation but also to a lower rate of VLDL synthesis. No indications were found for a decreased efficiency of VLDL to LDL conversion in Cholestyramine-fed animals.

Helmut F Erbersdobler - One of the best experts on this subject based on the ideXlab platform.

  • impact of β cyclodextrin and resistant starch on bile acid metabolism and fecal steroid excretion in regard to their hypolipidemic action in hamsters
    Biochimica et Biophysica Acta, 1999
    Co-Authors: Elke A Trautwein, Karin Forgbert, Dorte Rieckhoff, Helmut F Erbersdobler
    Abstract:

    Abstract To examine the impact on bile acid metabolism and fecal steroid excretion as a mechanism involved in the lipid-lowering action of β-cyclodextrin and resistant starch in comparison to Cholestyramine, male golden Syrian hamsters were fed 0% (control), 8% or 12% of β-cyclodextrin or resistant starch or 1% Cholestyramine. Resistant starch, β-cyclodextrin and Cholestyramine significantly lowered plasma total cholesterol and triacylglycerol concentrations compared to control. Distinct changes in the bile acid profile of gallbladder bile were caused by resistant starch, β-cyclodextrin and Cholestyramine. While Cholestyramine significantly reduced chenodeoxycholate independently of its taurine–glycine conjugation, β-cyclodextrin and resistant starch decreased especially the percentage of taurochenodeoxycholate by −75% and −44%, respectively. As a result, the cholate:chenodeoxycholate ratio was significantly increased by 100% with β-cyclodextrin and by 550% with Cholestyramine while resistant starch revealed no effect on this ratio. β-Cyclodextrin and resistant starch, not Cholestyramine, significantly increased the glycine:taurine conjugation ratio demonstrating the predominance of glycine conjugated bile acids. Daily fecal excretion of bile acids was 4-times higher with 8% β-cyclodextrin and 19-times with 1% Cholestyramine compared to control. β-Cyclodextrin and Cholestyramine also induced a 2-fold increase in fecal neutral sterol excretion, demonstrating the sterol binding capacity of these two compounds. Resistant starch had only a modest effect on fecal bile acid excretion (80% increase) and no effect on excretion of neutral sterols, suggesting a weak interaction with intestinal steroid absorption. These data demonstrate the lipid-lowering potential of β-cyclodextrin and resistant starch. An impaired reabsorption of circulating bile acids and intestinal cholesterol absorption leading to an increase in fecal bile acid and neutral sterol excretion is most likely the primary mechanism responsible for the lipid-lowering action of β-cyclodextrin. In contrast, other mechanisms involving the alterations in the biliary bile acid profile or repressed hepatic lipogenesis, e.g., VLDL production, appear to be involved in the hypolipidemic effect of resistant starch.

Lien B. Nguyen - One of the best experts on this subject based on the ideXlab platform.

  • sitosterolemia opposing effects of Cholestyramine and lovastatin on plasma sterol levels in a homozygous girl and her heterozygous father
    Metabolism-clinical and Experimental, 1996
    Co-Authors: Gerald Salen, Lien B. Nguyen, Margaret M Cobb, Stephen G Tint, Joshua Greenspan
    Abstract:

    Sitosterolemia is a genetic disorder characterized by sitosterol accumulation in plasma and clinically accelerated atherosclerosis. Under a condition of metabolic control with a 30% fat, low-sitosterol diet, we compared the effects of monotherapy and dual-drug treatment with lovastatin and Cholestyramine on plasma sterol parameters and endogenous cholesterol synthesis in a homozygous sitosterolemic patient with concomitant heterozygous familial hypercholesterolemia (FH), her obligate heterozygous father, and hyperlipidemic control subjects. We found that for both the sitosterolemic homozygote and heterozygote, Cholestyramine plus lovastatin dual therapy proved not to be superior to either drug treatment alone. In the homozygous patient, Cholestyramine accounted for the decrease of plasma sterol (ie, lovastatin was ineffective), whereas in the heterozygote, lovastatin represented the margin of difference (ie, low-dose Cholestyramine was relatively ineffective). Thus, the best treatment option for this homozygote child and her heterozygote father appears to be monotherapy with Cholestyramine and lovastatin, respectively. Stimulation by bile acid malabsorption produced a dramatic decrease of plasma sterols in the homozygote, without increasing endogenous cholesterol synthesis, but this therapy was ineffective in the heterozygote. Decreasing endogenous cholesterol synthesis with lovastatin was effective in the heterozygote, but ineffective in the homozygote. In suspected sitosterolemia, a poor sterol response to lovastatin and a dramatic response to Cholestyramine may differentiate homozygous from heterozygous and other familial forms of hyperlipidemia.

  • Differing effects of cholesterol and taurocholate on steady state hepatic HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities and mRNA levels in the rat.
    Journal of lipid research, 1992
    Co-Authors: Sarah Shefer, Gerald Salen, Ashok K. Batta, Lien B. Nguyen, Gene C. Ness, Indu R. Chowdhary, S Lerner, G. Stephen Tint
    Abstract:

    We investigated the effects of cholesterol, Cholestyramine, and taurocholate feeding on steady state specific activities and mRNA levels of hepatic 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase and cholesterol 7 alpha-hydroxylase in the rat. Interruption of the enterohepatic circulation of bile acids (Cholestyramine feeding) increased total HMG-CoA reductase activity 5-fold. Cholesterol and taurocholate administration suppressed total microsomal HMG-CoA reductase activities 87% and 65%, respectively. HMG-CoA reductase mRNA levels increased 3-fold with Cholestyramine, did not decrease significantly with cholesterol feeding, but were markedly decreased after taurocholate treatment. Cholesterol 7 alpha-hydroxylase activity increased 4-fold with Cholestyramine and 29% during cholesterol feeding, but decreased 64% with taurocholate. Cholesterol 7 alpha-hydroxylase mRNA levels rose 150% and 50% with Cholestyramine and cholesterol feeding, respectively, but decreased 73% with taurocholate. The administration of cholesterol together with taurocholate prevented the decline in cholesterol 7 alpha-hydroxylase mRNA levels, but inhibition of enzyme activity persisted (-76%). Hepatic microsomal cholesterol concentrations increased 2-fold with cholesterol feeding but did not change with taurocholate or Cholestyramine treatment. These results demonstrate that mRNA levels of HMG-CoA reductase are controlled by the hepatic taurocholate flux, whereas mRNA levels of cholesterol 7 alpha-hydroxylase are controlled by the cholesterol substrate supply. These end products, cholesterol and bile acids, exert post-transcriptional regulation on HMG-CoA reductase and cholesterol 7 alpha-hydroxylase, respectively.