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Systemic bile acids induce insulin resistance in a TGR5-independent manner.
Syring KE, Cyphert TJ, Beck TC, Flynn CR, Mignemi NA, McGuinness OP
(2019) Am J Physiol Endocrinol Metab 316: E782-E793
MeSH Terms: Animals, Bile Acids and Salts, Cholagogues and Choleretics, Cholic Acids, Deoxycholic Acid, Gene Expression Profiling, Gluconeogenesis, Glucose Clamp Technique, Hep G2 Cells, Hepatocytes, Humans, Insulin Resistance, Liver, Mice, Mice, Knockout, Obesity, Primary Cell Culture, Receptors, G-Protein-Coupled, Taurocholic Acid
Show Abstract · Added April 15, 2019
Bile acids are involved in the emulsification and absorption of dietary fats, as well as acting as signaling molecules. Recently, bile acid signaling through farnesoid X receptor and G protein-coupled bile acid receptor (TGR5) has been reported to elicit changes in not only bile acid synthesis but also metabolic processes, including the alteration of gluconeogenic gene expression and energy expenditure. A role for bile acids in glucose metabolism is also supported by a correlation between changes in the metabolic state of patients (i.e., obesity or postbariatric surgery) and altered serum bile acid levels. However, despite evidence for a role for bile acids during metabolically challenging settings, the direct effect of elevated bile acids on insulin action in the absence of metabolic disease has yet to be investigated. The present study examines the impact of acutely elevated plasma bile acid levels on insulin sensitivity using hyperinsulinemic-euglycemic clamps. In wild-type mice, elevated bile acids impair hepatic insulin sensitivity by blunting the insulin suppression of hepatic glucose production. The impaired hepatic insulin sensitivity could not be attributed to TGR5 signaling, as TGR5 knockout mice exhibited a similar inhibition of insulin suppression of hepatic glucose production. Canonical insulin signaling pathways, such as hepatic PKB (or Akt) activation, were not perturbed in these animals. Interestingly, bile acid infusion directly into the portal vein did not result in an impairment in hepatic insulin sensitivity. Overall, the data indicate that acute increases in circulating bile acids in lean mice impair hepatic insulin sensitivity via an indirect mechanism.
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19 MeSH Terms
Detergent enhancement of on-tissue protein analysis by matrix-assisted laser desorption/ionization imaging mass spectrometry.
Mainini V, Angel PM, Magni F, Caprioli RM
(2011) Rapid Commun Mass Spectrom 25: 199-204
MeSH Terms: Animals, Brain Chemistry, Cholic Acids, Detergents, Liver, Mice, Molecular Imaging, Myocardium, Octoxynol, Polysorbates, Proteins, Sodium Dodecyl Sulfate, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Surface-Active Agents, Whole Body Imaging
Show Abstract · Added March 3, 2020
Matrix-Assisted Laser Desorption/Ionization (MALDI) Imaging Mass Spectrometry (IMS) is a molecular technology that allows simultaneous investigation of the content and spatial distribution of molecules within tissue. In this work, we examine different classes of detergents, the anionic sodium dodecyl sulfate (SDS), the nonionic detergents Triton X-100, Tween 20 and Tween 80, and the zwitterionic 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) for use in MALDI IMS of analytes above m/z 4000. These detergents were found to be compatible with MALDI MS and did not cause signal suppression relative to non-detergent applications and did not produce interfering background signals. In general, these detergents enhanced signal acquisition within the mass range m/z 4-40 000. Adding detergents into the matrix was comparable with the separate application of detergent and matrix. Evaluation of spectra collected from organ-specific regions of a whole mouse pup section showed that different detergents perform optimally with different organs, indicating that detergent selection should be optimized on the specific tissue for maximum gain. These data show the utility of detergents towards enhancement of protein signals for on-tissue MALDI IMS analysis.
Copyright © 2010 John Wiley & Sons, Ltd.
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MeSH Terms
Selective antagonism of the hepatic glucocorticoid receptor reduces hepatic glucose production.
Edgerton DS, Jacobson PB, Opgenorth TJ, Zinker B, Beno D, von Geldern T, Ohman L, Scott M, Neal D, Cherrington AD
(2006) Metabolism 55: 1255-62
MeSH Terms: Animals, Blood Glucose, Cholic Acids, Dogs, Estrone, Glucagon, Glucose, Glucose Clamp Technique, Kinetics, Liver, Receptors, Glucocorticoid
Show Abstract · Added December 10, 2013
A liver-selective glucocorticoid (GC) receptor antagonist (A-348441) was used to determine the effect of reduced hepatic GC signaling on hepatic glucose production. Fasted conscious dogs were studied in the presence (GRA, n = 6) or absence (CON, n = 6) of the intraduodenally administered GC receptor antagonist (100 mg/kg). All dogs were maintained on a pancreatic clamp and in a euglycemic state for 7 hours to ensure that any changes in glucose metabolism were the direct result of the effects of A-348441, which was given at the start of a 5-hour experimental period. In the GRA group, the arterial plasma insulin level was 4.6 +/- 0.7 and 4.8 +/- 0.6 microU/mL during the basal and the last 30 minutes of the experimental periods, respectively. In the CON group, it was 4.0 +/- 0.3 and 4.5 +/- 0.5 microU/mL in the 2 periods, respectively. The arterial plasma glucagon level was 49 +/- 4 and 46 +/- 3 pg/mL in the 2 periods in the GRA group, and 45 +/- 3 and 42 +/- 3 pg/mL in the CON group. Net hepatic glucose balance progressively decreased in the GRA group from 1.31 +/- 0.18 to 0.49 +/- 0.30 mg/kg per minute, whereas in the CON group, net hepatic glucose balance was 1.17 +/- 0.09 and 1.43 +/- 0.18 mg/kg per minute during the basal and last 30 minutes of the experimental periods, respectively. No significant change in net renal or gut glucose balance or nonhepatic glucose uptake was observed in either group. This study demonstrates that the GC receptor plays an important role in the regulation of basal hepatic glucose production and represents a significant potential therapeutic target.
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11 MeSH Terms
Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes.
Jacobson PB, von Geldern TW, Ohman L, Osterland M, Wang J, Zinker B, Wilcox D, Nguyen PT, Mika A, Fung S, Fey T, Goos-Nilsson A, Grynfarb M, Barkhem T, Marsh K, Beno DW, Nga-Nguyen B, Kym PR, Link JT, Tu N, Edgerton DS, Cherrington A, Efendic S, Lane BC, Opgenorth TJ
(2005) J Pharmacol Exp Ther 314: 191-200
MeSH Terms: 3T3 Cells, Adipocytes, Animals, Biotransformation, Blood Glucose, Cell Differentiation, Cholic Acids, Diabetes Mellitus, Type 2, Dogs, Drug Synergism, Estrone, Glucocorticoids, Glucose, Glutamate-Ammonia Ligase, Hypoglycemic Agents, Liver, Male, Mice, Obesity, Prednisolone, Rats, Rats, Zucker, Receptors, Glucocorticoid, Reverse Transcriptase Polymerase Chain Reaction, Rosiglitazone, Thiazolidinediones, Tyrosine Transaminase
Show Abstract · Added December 10, 2013
Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.
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27 MeSH Terms
The metabolism of 3alpha, 7alpha, 12alpha-trihydorxy-5beta-cholestan-26-oic acid in two siblings with cholestasis due to intrahepatic bile duct anomalies. An apparent inborn error of cholic acid synthesis.
Hanson RF, Isenberg JN, Williams GC, Hachey D, Szczepanik P, Klein PD, Sharp HL
(1975) J Clin Invest 56: 577-87
MeSH Terms: Adult, Bile, Bile Acids and Salts, Bile Ducts, Intrahepatic, Chemical Phenomena, Chemistry, Child, Cholestasis, Cholic Acids, Female, Humans, Infant, Male, Mass Spectrometry, Metabolism, Inborn Errors, Sterols
Show Abstract · Added March 20, 2014
Studies were carried out in a family in which two children with cholestasis due to intrahepatic bile duct anomalies were shown to have increased amounts of the cholic acid precursor, 3alpha, 7alpha, 12alpha-trihydorxy-5beta-cholestan-26-oic acid (THCA). The metabolism of THCA was studied in one of these patients after an intravenous injection of (3H)THCA, and the cause of the increased amounts of THCA in this condition was found to be due to a metabolic defect in the conversion of this compound into cholic acid. A small amount of (3H)cholic acid was also identified after (3H)THCA administration, confirming that this metabolic defect was incomplete. Varanic acid (3alpha, 7alpha, 12alpha, 24xi-tetrahydorxy-5beta-cholestan-26-oic acid), a metabolite of THCA, could not be identified in either of these patients. By assuming that this compound would be conjugated and excreted if the metabolic block occurred after the formation of varanic acid, the defect in these patients appears to be due to a deficiency of a 24-hydroxylating enzyme system required to convert THCA into varanic acid. This condition appears to be transmitted in an autosomal recessive fashion, because the two affected patients were of opposite sex, and neither a normal sibling nor the two parents have increased amount of THCA in their bile.
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16 MeSH Terms
Synthesis of 11, 12-2H2- and 11, 12-3H2-labeled chenodeoxycholic and lithocholic acids.
Cowen AE, Hofmann AF, Hachey DL, Thomas PJ, Belobaba DT, Klein PD, Tökes L
(1976) J Lipid Res 17: 231-8
MeSH Terms: Chenodeoxycholic Acid, Cholanes, Cholenes, Cholic Acids, Deuterium, Drug Stability, Feces, Humans, Isotope Labeling, Lithocholic Acid, Mass Spectrometry, Oxidation-Reduction, Tritium
Show Abstract · Added March 20, 2014
Deuterium- and tritium-labeled chenodeoxycholic acid and lithocholic were prepared by catalytic reduction of their respective delta11 derivatives. Structures of the intermediates and their isotopic purity were verified by chemical ionization and electron impact mass spectrometry and by nuclear magnetic resonance spectroscopy. Experimental conditions for reductive deuteration were defined which gave complete reduction of the olefin and a product of high isotopic purity. Conditions for optimal tritiation were developed with which little exchange of protons with the solvent occurred; the product had high specific activity. To test biological stability of the label, the 3H-labeled chenodeoxycholic acid was administered simultaneously with 14C-labeled chenodeoxycholic acid to two healthy subjects and the 3H/14C ratio in bile was determined daily for several days. The ratio remained identical to that administered, suggesting that the 11,12-3Hlabel in chenodeoxycholic acid is stable during enterohepatic cycling and can be used for valid estimates fo bile acid kinetics in many by the isotope dilution technique.
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13 MeSH Terms
Hepatic lesions and hemolysis following administration of 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oyl taurine to rats.
Hanson RF, Williams GC, Hachey D, Sharp HL
(1977) J Lab Clin Med 90: 536-48
MeSH Terms: Anemia, Hemolytic, Animals, Bile, Bile Acids and Salts, Cholic Acids, Endoplasmic Reticulum, Female, Hemoglobinuria, Humans, Liver, Liver Cirrhosis, Mitochondria, Liver, Rats, Taurine, Taurocholic Acid
Show Abstract · Added March 20, 2014
Patients with a metabolic block in the conversion of THCA into cholic acid develop cirrhosis and hemolysis, and die of hepatic failure. In these patients, THCA is largely conjugated to taurine (tauro-THCA) and excreted instead of being converted into cholic acid. In the present study, the effects of tauro-THCA on hemolysis, bile flow, and hepatic morphology were evaluated in bile fistula rats. All rats infused with tauro-THCA at rates of 0.25, 0.50 or 0.75 micronmol/min developed hemolysis with hemoglobinuria. A direct toxic effect of tauro-THCA on washed human red blood cell membranes was demonstrated at a concentration of 8 X 10(-4) M. Liver biopsy sections from rats infused for a 2 hr period with tauro-THCA were examined by electron microscopy and showed dilation of the rough endoplasmic reticulum and distortion of mitochondrial membranes. Cholestasis was not induced, since tauro-THCA actually caused a greater choleretic response for a given rate of bile salt excretion than did taurocholate. This study raises the possibility that the clinical liver disease seen in patients with a metabolic block in the conversion of THCA into cholic acid may be caused by tauro-THCA.
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15 MeSH Terms