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1
Li, Hai. "Bile acids enterohepatic circulation". [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2005. http://dare.uva.nl/document/77982.
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Zhu, Xiao Xia. "Binding interactions of bile acids and bile pigments with amines". Thesis, McGill University, 1988. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=75846.
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The binding of selected bile acids and bile pigments by peptides and quaternary amines has been studied by adsorption and NMR experiments. Novel adsorbents with quaternized peptide-containing functional groups for bile acids have been prepared by solid phase peptide synthesis techniques. The adsorption studies, conducted in aqueous buffer solutions, show that these resins have an enhanced capacity, on a per active site basis, and improved specificity over cholestyramine and colestipol. The interaction between bile acid anions and the pendants is predominantly ionic linkage, although hydrophobic and other interactions are also important. An NMR study of the binding between bile acids and various ligands, including peptides, by the determination of carbon-13 spin-lattice relaxation times, confirms the ionic and hydrophobic interactions which occur cooperatively and simultaneously.New adsorbents for bilirubin have been prepared by covalently coating a water-swellable polyamide resin with polypeptides. These resins have much higher capacities for bilirubin in aqueous buffer solution than cholestyramine and improved capacities over the resins with attached oligopeptide pendants. The binding behavior of the resin coated with poly- sc D-lysine is the same as that of poly- sc L-lysine. The amount of bilirubin adsorbed by these resins is directly proportional to the number of lysine residues on the resin, which is consistent with the formation of an ionic linkage. This is confirmed by a study of the interaction of bilirubin with an oligopeptide, sc L-lysyl- sc L-lysine, by measurements of proton and carbon-13 NMR spin-lattice relaxation times combined with nitrogen-15 NMR experiments. The $ sp{15}$N NMR spectra of bilirubin and some related bile pigments have also been assigned by two-dimensional $ sp{15}$N-$ sp1$H heteronuclear correlation experiments.
3
Rao, Girish. "Enzyme electrode studies of bile acids". Thesis, Imperial College London, 1990. http://hdl.handle.net/10044/1/11881.
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Bradburn, David Michael. "Bile acids and short fatty acids in familial adenomatous polyposis". Thesis, University of Newcastle Upon Tyne, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308760.
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Trusova, Tatyana. "Quantitative estimation of bile acid conjugates in human bile using HPLC /". Connect to online version, 1995. http://hdl.handle.net/1989/3555.
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Qian, Jiang. "Studies of Sulfur Reduction of Taurine and Taurine-Conjugated Bile Acids by Bile acid 7α-Dehydroxylating Bacteria". TopSCHOLAR®, 2000. http://digitalcommons.wku.edu/theses/694.
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Bile acids are C24 steroids that are derived in the liver from cholesterol and secreted into the intestinal lumen to aid in emulsification of dietary lipids and lipid-soluble vitamins. The indigenous intestinal microflora modify bile acids, producing up to 20 unique bile acid metabolites. The 7α-dehydroxylation of the bile acids is the most physiologically important bile acid biotransformation. All known intestinal bacteria capable of bile acid 7α-dehydroxylation are anaerobic, gram-positive rods of the genera Clostridium and Eubcicterium. Bile acid 7α-dehydroxylating bacteria often contain bile salt hydrolase, which hydrolyzes the peptide bond in taurine-conjugated bile acids to yield a free bile acid and taurine. Taurine is an organosulfonate containing a sulfite moiety. There have been no published reports indicating whether 7α-dehydroxylating bacteria can utilize taurine. Given that taurine and taurine-conjugated bile acids are found at great concentrations in the intestine, the ability to utilize the compound would confer a competitive advantage to these bacteria. In this study, the ability of 7α-dehydroxylating bacteria to dissimilate taurine and taurine-conjugated bile acids produce hydrogen sulfide was investigated. First, hydrogen sulfide produced by bile acid 7α-dehydroxylating bacteria cultured in tryptic soy broth and semi-defined media from taurine and taurine-conjugated bile acids was qualitatively detected by inclusion of ferric ammonium citrate in the media. The results obtained from trials utilizing anaerobic tryptic soy broth and from semi-defined medium were not consistent, suggesting that qualitative determination of sulfide by inclusion of ferric ammonium citrate is inconclusive. Then hydrogen sulfide produced by bile acid 7α-dehydroxylating bacteria cultured in modified semi-defined medium (not containing a reducing agent) over time in the presence or absence of taurine-conjugated bile acids was quantified using the methylene blue method. Sulfide concentrations in medium cultured with two different strains of bile acid 7α-dehydroxylating bacteria, Eubcicterium sp. 12708 and Clostridium sp. HD-17, in presence of 100 |j.M or 5 mM sulfonates were not significantly higher than those in the absence of sulfonate. In addition, the highest sulfide concentration determined from medium cultured with two different strains of bile acid 7α-dehydroxylating bacteria for a period of five days was not above backgroud level. These data demonstrated that these two bile acid 7α-dehydroxylating bacteria, Eubcicterium sp. 12708 and Clostridium sp. HD-17, are not capable of desulfonating taurine and taurineconjugated bile acids to produce hydrogen sulfide under the conditions tested.
7
McNeilly, Alison Delamere. "The impact of bile acids on glucocorticoid metabolism". Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/24968.
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The work in this thesis demonstrates that bile acids and their conjugates are competitive inhibitors of glucocorticoid metabolism by both 11β-HSD1 and 5β-reductase in liver. In vivo, in male Wistar rats, manipulation of hepatic bile acid concentrations by dietary supplementation with chenodeoxycholic acid (CDCA; 1% w/w) suppressed activities of hepatic 5β-reductase and 11βHSD1 activity and caused a reduction in total urinary (mainly 5β-reduced) glucocorticoid metabolites. In response to acute restraint stress bile acid treated animals showed a delay in return to basal corticosterone levels indicative of altered clearance. In addition, adrenal weight and lipid accumulation within the adrenal gland was reduced in bile acid treated animals. Stimulation of bile acid synthesis by cholestyramine (5% w/w) reduced hepatic 5β-reductase activity with animals excreting fewer urinary total (mainly 5β-reduced) glucocorticoid metabolites. Conversely, a reduction in hepatic bile acid content via administration of a fat-free diet, induced hepatic 5β-reductase activity accompanied by an increase in total, principally 5β-reduced, urinary metabolites. Animals fed the fat-free diet had larger adrenal glands, and suppressed circulating corticosterone, again suggesting altered HPA axis regulation. These findings were pursued in rats with bile duct ligation, a pathological model of elevated bile acids. In these animals, reduced activities of 5β-reductase and 11β-HSD1 were also identified. Lastly investigations were made of the impact of bile acids on the renin-angiotensin-aldosterone system (RAAS). Manipulations which increased bile acids concentrations were predicted to reduce the rate of aldosterone inactivation, since it too is a substrate for 5β-reductase. Treatments increasing bile acids were accompanied by a renin-independent increase in aldosterone and associated sodium retention.
8
Leonard, Danièle. "Adsorption of bile acids by ion-exchange resins". Thesis, McGill University, 1989. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=74309.
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The interactions of cholestyramine with bile acids in aqueous buffer solutions were studied by in vitro adsorption experiments. Application of the Donnan theory, which is based on ion partitioning between two phases, indicates that the adsorption is an ion-exchange process--the bile acid anion displaces the chloride counter-ion of cholestyramine. Donnan considerations indicate that the bile acid in the resin phase exists in two forms, bound and unbound, but at higher Ceq the bound form is increasingly favoured. Since the concentrations of bound bile acid in the resin phase are above the critical micellar concentration, micelle-type ordering is occurring. It is also possible that the unbound bile acid in the resin phase aggregates to form "regular" micelles. The micellization promotes the partitioning of glycocholic acid into the resin phase, explaining the ability of cholestyramine to adsorb glycocholic acid significantly, in vitro.Ion-exchange resins were prepared by solid phase peptide synthesis with active sites chosen to resemble those of cholestyramine. They were produced by coupling 4-(aminomethyl)benzoic acid, 4-aminophenylacetic acid or 4-(aminomethyl)phenylacetic acid to the backbone. The ion-exchange resins were prepared both as primary amines and in the quaternized form. The cholestyramine-like sorbents were synthesized with systematic changes in the structure, to determine which structural parts of cholestyramine are involved in the adsorption process. As compared to cholestyramine, both sets of resins were remarkably ineffective in adsorbing bile acids in vitro. It was found that the nature of the backbone determines the accessibility to the active site; that the resins with the methylene group positioned between the phenyl group and the amino group have higher adsorption capacity for glycocholic acid; and that quaternization increases the adsorption capacity. The two latter observations indicate the importance of the basicity of the active site. Therefore, in cholestyramine, the backbone is such that it permits the transfer of ionic species and the quaternary ammonium group is involved in the interaction with bile acids.
Computer modelling showed that the cholestyramine pendants are close to one another and are separated by benzene rings, thus leaving too little space between them to allow a bile acid molecule to interact with the benzene rings. Therefore, the bile acids must interact with the quaternary ammonium group, leaving the bile acid molecule inside the cavity where they interact with one another to form micelles. The possible modes of interactions of bile acids with the synthesized resins are more numerous since the pendants are not as close together. (Abstract shortened by UMI.)
9
Zeck, Lisa. "Optimization of an immobilized enzyme system for conjugated bile acids /". Connect to online version, 1995. http://hdl.handle.net/1989/3548.
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Barker, Gillian M. "Bile acids and neutral sterols in familial adenomatous polyposis". Thesis, University of Aberdeen, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308002.
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In familial adenomatous polyposis (FAP), inactivation of the APC gene is directly linked to the development of gastrointestinal polyps and cancer. It is likely that other epigenetic factors are involved in the malignant change of polyp to carcinoma. Previous studies have implied an abnormal bile acid profile, both in faeces and bile. In this study, using carefully matched control groups, extraction of bile acids from faeces and bile was performed and analysis was rigorously performed using Gas-liquid chromatography-Mass Spectrometry. No significant differences were found between the two groups in the profile of major bile acids. An increased faecal excretion of two minor bile acids, 5β-cholanoic acid-3α-ol-12-one and 5α-cholanoic acid-3α-ol-12-one and an increased level of 5β-cholanoic acid-3α-01-12-one in bile was found in patients with FAP. A difference in the faecal neutral sterol profile had also been suggested, but this study showed no significant difference between the two groups when matching controls are used. This study does not support the idea that there are significant differences in faecal bile acid, biliary bile acid or neutral sterol profiles between individuals with familial adenomatous polyposis and controls.
11
Badiee, Mohsen. "Mechanistic Insights intoThe Physiology of Bile acids and Retinoids". Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1505919467280191.
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Nguyen, Elizabeth Ann Gaddi. "The Regulation of Bile Acids on NHE8 Gene Expression". Thesis, The University of Arizona, 2013. http://hdl.handle.net/10150/297714.
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Sodium is an essential electrolyte necessary to keep multiple systems in the human body functional. Knowledge of sodium-proton exchanger will give rise to multiple clinical applications to diseases that affect our current population, which is why I personally am interested in conducting research in this field. In order to understand GW 4064 effect on NHE8 gene expression, protein and RNA expression were investigated via treatment at different concentrations and different time intervals through Western blotting and Real-Time PCR Analysis. To find the mechanism behind GW 4064 effects on NHE 8 expression, the PGL3 FXR promoter was utilized to see if GW 4064 inhibitory mechanism was through transcription or translation. Expression, stimulation, and inhibition were determined via numerical calculations. From the resulting data, we can conclude that GW 4064 inhibition of NHE8 protein and RNA expression occurs via transcription.
13
Ellis, Ewa C. S. "Use of primary human hepatocytes for elucidation of bile acid synthesis /". Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-424-0.
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Bajor, Antal. "Bile acid induced diarrhoea : pathophysiological and clinical aspects /". Göteborg : Dept. of Internal Medicine, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, 2008. http://hdl.handle.net/2077/9840.
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Murphy, Charlotte. "Studies on the regulatory roles of cholesterol and bile acids /". Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-173-9/.
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Kehring, Allysa. "Bile Acids to Predict the Developments of Neonatal Necrotizing Enterocolitis". Thesis, The University of Arizona, 2010. http://hdl.handle.net/10150/146074.
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This honors thesis analyzes the methodology and results of ongoing research on the potential use of bile acid concentrations in neonatal stool to be used as an indicator for the onset of the disease necrotizing enterocolitis (NEC). NEC is a serious complication in a premature infant with the potential for death. Twenty-two patients were enrolled in the study over the period of eight months, however, no patient developed NEC. Control patients were analyzed for trends in bile acid concentrations. Elevation of in bile acid concentration were seen following each feeding. Previous inclinations were also proven in regards to that mother's milk is more easily digested and remains a more nutritionally sound form of feeding than formula milk.
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Tierney, Juliann Jude. "The synthesis and testing of novel cholic acid based stationary phases". Thesis, University of Bristol, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247854.
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Jean-Louis, Samira. "Membrane Perturbation By Bile Acids and Their Potential Role in Signaling". Tucson, Arizona : University of Arizona, 2006. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1471%5F1%5Fm.pdf&type=application/pdf.
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Lowe, Gordan M. "Biochemical and genetic aspects of the microbial degradation of bile acids". Thesis, Liverpool John Moores University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305858.
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Obuseng, Veronica Conie. "Bile acids as indicator of faecal inputs into soils and sediments". Thesis, University of Bristol, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391155.
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Elhmmali, Mohamed Mimoun. "Complementary use of bile acids and sterols as sewage pollution indicators". Thesis, University of Bristol, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245524.
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Jean-Louis, Samira. "Membrane Perturbation By Bile Acids and Their Potential Role in Signaling". Diss., The University of Arizona, 2005. http://hdl.handle.net/10150/193551.
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Secondary bile acids have long been postulated to be tumor promoters in the colon but their mechanism of action are yet to be delineated. Though most bile acids are chemically similar, they have been found to exert contrasting signaling effects in the colonic epithelium. Particularly, hydrophobic bile acids such as deoxycholic acid (DCA) are found to be tumor promoters while their hydrophilic counterparts such as ursodeoxycholic acid (UDCA) are chemopreventive. Given the fact that colon cells do not possess bile acid transporters, the question that arises is how do bile acids activate intracellular signaling? In our studies, we examined the actions of bile acids at the cell membrane and found that hydrophobic bile acids can perturb membrane structure. This membrane perturbation was found to be characterized by a change in membrane fluidity and by cholesterol aggregation. Additionally, several membrane associated proteins were found to be deregulated in response to DCA further supporting the above conclusion regarding membrane perturbation. Moreover, caveolin, a negative regulator of membrane microdomains was seen to be dephosphorylated and disassociated from the membrane microdomains, implicating membrane microdomains as a possible target of the effects of DCA on the membrane. Consistent with this, we found that DCA was able to cause rapid and sustained activation of the receptor tyrosine kinase, EGFR and that this activation was ligand-independent. Using fluorescent-tagged bile acids we showed increased aggregation and clustering in the membranes treated with FITC-DCA in a manner that was reminiscent of receptor activation in immune cells. Collectively, these data suggest that bile-acid induced signaling is likely to be initiated through alterations of the plasma membrane structure in colon cancer cells.
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Opiyo, Monica Naomi. "The role of glucocorticoid metabolism in bile acid homeostasis". Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25673.
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Alterations in glucocorticoid (GC) biosynthesis and metabolism are associated with a variety of pathophysiological disorders including cholestasis, diabetes and other metabolic disorders. Bile acids (BA) are also important modulators of metabolic functions and regulate cholesterol, triglyceride and glucose homeostasis as well as being critical for dietary fat digestion, enterohepatic function, and postprandial thermogenesis. In intact cells and in vivo, the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme converts inactive GC precursors (cortisone in humans, and 11-dehydrocorticosterone in mice and rats) into their active forms (cortisol and corticosterone, respectively) thereby amplifying local intracellular GC levels. Interconversion by 11β-HSD1 of other sterols has also been described. These include conversions of 7keto-cholesterol to 7β-hydroxycholesterol, 7-oxodehydroepiandrosterone (7-oxo-DHEA) to 7α-hydroxy- and 7β-hydroxy DHEA, 7- oxo-lithocholic acid (LCA, a bile acid; BA) to chenodeoxycholic acid (CDCA, a 7α- hydroxylated BA) and ursodeoxycholic acid (UDCA, a 7β-hydroxylated BA) in human liver microsomes. In the liver, BA inhibit 11β-HSD1 but whether 11β-HSD1 regulates BA homeostasis is unclear. Evidence of molecular regulation of the enterohepatic recycling of bile acids by liver glucocorticoid receptor (GR) in mice does suggest a role for 11β-HSD1. It was therefore hypothesised that disruption of 11β-HSD1 expression in mice would impair BA recycling and might affect the relative concentrations of BA within the enterohepatic circuit. The primary objective of the current work was to investigate the impact of altered 11β-HSD1 on BA homeostasis. This was achieved using genetically modified mouse models with altered 11β-HSD1 expression, either globally or restricted to hepatocytes. BA are stored in the gall bladder and are released postprandially, to aid digestion. It was hypothesised that 11β-HSD1 deficiency might the affect the process of postprandial gall bladder emptying/refilling. Mice with global 11β-HSD1 knockout (Hsd11b1-/-) and age-matched control mice (C57Bl/6) were either fasted for 4h and culled or fasted for 4h and re-fed for another 4h before culling. Their response to fasting and re-feeding was assessed with specific focus on organs associated with BA recycling in the enterohepatic circuit (liver, gall bladder, serum and small intestine). Gall bladders of fasted Hsd11b1-/- and C57Bl/6 mice had similar volumes of bile but in fasted Hsd11b1-/- mice, BA concentrations were higher in serum and liver. As expected, re-feeding caused gall bladder emptying in C57Bl/6 mice with consequent increased serum and liver bile acid concentrations. In Hsd11b1-/- mice, the gall bladder did not empty and serum and liver BA concentrations were similar to the fasted state. To explore possible reasons for this, levels of mRNA encoding proteins known to be involved in hepatic BA transport were quantified using real-time q-PCR. Levels of mRNA encoding NTCP/ SCL10A1/ SCL10A1, the transporter responsible for most hepatocyte BA uptake, were increased in livers of fasted Hsd11b1-/- mice whereas levels of Slc51b mRNA, encoding the OST- transporter that facilitates BA removal from liver to the systemic circulation, and levels of Mrp2 and Atp8b1/FIC1 mRNAs (both encoding proteins which transport BA from liver into gall bladder) were decreased. This suggests that in fasted Hsd11b1-/- mice, BA transporter expression is altered to increase BA influx into hepatocytes and decrease efflux, to compensate for reduced levels of liver BA. These data together imply that bile acid recycling is controlled by 11β-HSD1 activity which regulates gall bladder emptying, hepatic BA concentration and BA transporter activity to ensure continuity of BA recycling within the enterohepatic circuit compartments. These changes may also affect digestion of lipids and fat-soluble micronutrients. Because 11β-HSD1 can directly metabolise secondary BA, it was predicted that 11β-HSD1 deficiency would lead to changes in the BA profile. Profiling of BA in the gall bladder was performed using mass spectrophotometry. In Hsd11b1-/- mice, 7α-hydroxylated BA predominated (cholic acid [CA]>α-muricholic acid [α- MCA]>CDCA>others), in contrast to C57Bl/6 mice in which 7β-hydroxylated BA predominated (ω-MCA>β-MCA>UDCA>others). The ratio of 7α:7β acids was therefore >100-fold greater in Hsd11b1-/- mice. This suggests that 11β-HSD1 either directly or indirectly controls the epimerisation of 7α- to 7β- hydroxylated BAs. Measurement of mRNAs encoding proteins important for hepatic BA biosynthesis in livers of fasted Hsd11b1-/- mice showed decreased expression of Scarb1/SR-B1, Cyp39a1 and Cyp27a1 (though with no change in levels of CDCA, the product of CYP27A1, in liver or bile fluid), compared to fasted control mice. Hepatic levels of Gpbar1/TGR5/GPBAR1 and Cyp3a11 mRNAs, encoding proteins important in BA detoxification, were increased and decreased, respectively. This suggests that Gpbar1/TGR5/GPBAR1, encoding G-protein coupled bile acid receptor (also called TGR5/GPBAR1) and an FXR target, could be induced to detoxify 7α-hydroxylated BA whereas expression of Cyp3a11, which catalyses the conversion of LCA to hyodeoxycholic acid (HDCA) is decreased; bile fluid of Hsd11b1-/- mice contained lower levels of LCA and little to no HDCA, though LCA and HDCA levels in liver were unaltered. Currently, the functional differences between 7α- and 7β- hydroxylated BA are not clear. However, these findings could have significant implications for bile acid-mediated transcription which, in turn, might affect lipid and sterol metabolism. Also, alterations in BA composition may have other physiological consequences via other pathways. Because cholesterol is the precursor of BA synthesis, it was hypothesised that western diet (WD) (containing cholesterol) would exacerbate and/or alter the phenotype of Hsd11b1-/- mice. Gall bladder weights of fasted Hsd11b1-/- and control C57Bl/6 mice did not change with western diet compared to chow diet. In control C57Bl/6 mice, the total BA concentration in the gall bladder increased in response to WD in comparison to chow diet. In contrast, Hsd11b1-/- mice showed no change in total BA concentration when fed on WD in comparison to chow. These data indicate that 11β-HSD1 is required by mice for the normal increase in total BA concentration in bile in response to dietary cholesterol. BA profiling of bile from control mice fed on WD showed no difference in the relative amounts of 7β-hydroxylated BA and 7α-hydroxylated BA to littermates fed on chow diet with the exception of β–MCA which increased, and α–MCA which decreased. Like chow-fed Hsd11b1-/- mice, BA profiling of bile from WD-fed Hsd11b1-/- mice showed a significant decrease in relative levels of 7β-hydroxylated BA (UDCA < β-MCA < others) and an increase in percentage of 7α-hydroxylated BAs (CA>α-MCA>CDCA>others) compared to C57Bl/6 controls. These data show that Hsd11b1-/- mice fail to show the normal increase in 7β-hydroxylated BA and decrease in 7α-hydroxylated BA observed in control mice in response to a cholesterol containing diet, suggesting 11β-HSD1 deficiency blunts the influence of cholesterol on BA composition. Measurement of hepatic mRNAs encoding BA transporters suggest that hepatocyte uptake of BA is decreased in C57Bl/6 on WD compared to those mice on chow diet, whereas this was not the case in Hsd11b1-/- mice where hepatic expression did not change with diet. Thus, Hsd11b1-/- mice failed to increase expression of Ntcp/ Scl10a1/ Scl10a1 appropriately, suggesting impaired hepatic BA uptake, while Slc51b (encoding OST-β) expression was increased, compared to control mice, possibly to reduce hepatic BA concentration by transporting BA out of hepatocytes into the systemic circulation. Therefore, Hsd11b1-/- mice may adapt to a cholesterol-induced increase in hepatic BA by blunting hepatic BA uptake via NTCP/ SCL10A1/ SCL10A1 and increasing hepatic efflux via OST-β. The effects of 11β-HSD1 deficiency upon BA recycling and BA profile and concentration within the enterohepatic circuit, could reflect 11β-HSD1 action within the liver or could be due to actions in other tissues.To investigate the role of hepatic 11β-HSD1 specifically, 11β-HSD1 liver-specific knockout (Hsd11b1LKO), 11β- HSD1 liver-specific over-expressors (Hsd11b1LOE) and control mice with exon 3 of the Hsd11b1 gene “floxed” (Hsd11b1F) were studied. Findings from this study indicate a role for 11β-HSD1 in adaption to dietary cholesterol and suggest that hepatic 11β-HSD1 (as opposed to 11β-HSD1 in extra-hepatic tissues) is the main factor regulating BA metabolism. Also, work from this thesis demonstrates 11β-HSD1 is an important regulator of gall bladder emptying and filling, an important component of enterohepatic bile acid recycling. Based on these findings it is anticipated that therapeutic use of 11β-HSD1 inhibitors will result in BA imbalances within the enterohepatic circuit and therefore BA homeostasis. Care must therefore be observed when implementing therapeutic use of 11β-HSD1 inhibitors, with particular focus on patients with cholestasis, Addison’s disease and critically ill patients who already have known BA imbalances in their enterohepatic system.
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Werry, Brian Scott. "Characterizing Bile Acid Association as a Ligand and in Micellization". Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1386186690.
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Harris, Spencer. "Discovery and characterization of bile acid and steroid metabolism pathways in gut-associated microbes". VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4713.
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The human gut microbiome is a complex microbial ecosystem residing in the lumen of our gastrointestinal tract. The type and amounts of microbes present in this ecosystem varies based on numerous factors, including host genetics, diet, and environmental factors. The human gut microbiome plays an important role in normal host physiological functions, including providing energy to colonocytes in the form of short-chain fatty acids. However, gut microbial metabolites have also been associated with numerous disease states. Current tools for analyzing the gut microbiome, such as high-throughput sequencing techniques, are limited in their predictive ability. Additionally, “-omic” approaches of studying the complex array of molecules, such as transcriptomics (RNA), proteomics (proteins), and metabolomics (previously identified physiologically active molecules), give important insight as to the levels of these molecules but do not provide adequate explanations for their production in a complex environment. With a better physiological understanding of why specific metabolites are produced by the gut microbiome, more directed therapies could be developed to target their production. Therefore, it is immensely important to study the specific bacteria that reside within the gut microbiome to gain a better understanding of how their metabolic actions might impact the host. Within this framework, this study aimed to better understand the production of secondary bile acid metabolites by bacterial in the gut microbiome. High levels of secondary bile acids are associated with numerous pathophysiological disorders including colon cancer, liver cancer, and cholesterol gallstone disease. In the current study, three bile acid metabolizing strains of bacteria that are known members of the gut microbiome were studied. A novel strain of Eggerthella lenta was identified and characterized, along with the type strain, for its ability to modulate bile acid and steroid metabolism based on the atmospheric gas composition. Additionally, it was shown that the oxidation of hydroxyl groups on primary bile acids by E. lenta C592 inhibited subsequent 7α-dehydroxylation by Clostridium scindens. The gene involved in the production of a Δ4,6-reductase enzyme, responsible for catalyzing two of the final reductive steps in the 7α-dehydroxylation pathway, was putatively identified and characterized in Clostridium scindens ATCC 35704. Lastly, the transcriptomic profile of Clostridium scindens VPI 12708 in the presence of numerous bile acids and steroid molecules was studied. These studies contribute significantly to the understanding of why specific bile acid metabolites are made by members of the gut microbiome and suggest ways of modulating their production.
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Chen, Fei Wen. "Lean NAFLD: A distinct entity shaped by differential metabolic adaptation". Thesis, The University of Sydney, 2020. https://hdl.handle.net/2123/22240.
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Non-alcoholic fatty liver disease (NAFLD) prevalence is growing dramatically with epidemic of obesity. A subset of patients with NAFLD is lean, but the pathophysiology of this sub-group is still not well known. This project aims to investigate the roles of metabolic health and metabolic adaptation in the pathogenesis of lean NAFLD, using well-characterised Caucasian subjects with lean and non-lean NAFLD, and comparing them with the lean and non-lean healthy controls, and murine models. We investigated in detail their demographics, genetic background, bile acid profile, gut microbiota and their bile acid regulatory activity to further understand the underlying pathophysiology governing the development and progression of lean NAFLD. We then compared our findings in humans with that of mice models of lean and non-lean NAFLD. Finally, we performed an untargeted metabolomics analysis on lean and non-lean NAFLD patients to determine other metabolic pathways and biomarkers, which may be relevant to lean NAFLD.
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Choucair, Ibrahim. "GUT MICROBE METABOLISM OF BILE ACIDS AND THEIR RELATIONSHIP TO CARDIOMETABOLIC DISEASES". Cleveland State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=csu1570190994304441.
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Milona, Alexandra. "Role of FXR in the adaptive response to bile acids during pregnancy". Thesis, Imperial College London, 2009. http://hdl.handle.net/10044/1/4727.
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The bile acid receptor FXR maintains bile acid homeostasis through the dynamic regulation of transporters, detoxification and biosynthesis enzymes. Intrahepatic cholestasis of pregnancy (ICP) is caused by disturbance in bile acid homeostasis in predisposed individuals. The first genetic variants in FXR, identified in an ICP population, are investigated in this thesis using in vitro approaches and a functional effect is demonstrated. Reproductive hormones are implicated in the aetiology of ICP but experiments in mice suggest that estrogen and progesterone alone are unlikely to be the cause of gestational cholestasis. Pregnancy increases the metabolic demand on the maternal liver and, in mice, causes maternal hepatomegaly that is associated with pro-cholestatic gene expression and raised serum and hepatic bile acids. Gestational hepatomegaly is characterised in detail for the first time and Fxr is shown to be required to maintain the normal mechanisms driving this process. Furthermore, pro-cholestatic gene expression and the fact that hepatic bile acids do not accumulate in pregnant Fxr-/- or cholate-fed mice suggest that for unknown reasons, gestation could be a period of reduced Fxr function. Conclusions: Pregnancy causes perturbed bile acid homeostasis in mice. This may be a result of Fxr playing a complex role in mediating, or responding to, the metabolic demands of gestation. Furthermore, FXR protects individuals from developing pregnancy-specific cholestatic disease.
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Mooranian, Armin. "Novel artificial cell microencapsulation of probucol and bile acids in diabetes mellitus". Thesis, Curtin University, 2018. http://hdl.handle.net/20.500.11937/70687.
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This thesis studied bile acids in the oral delivery of the anti-diabetic compound probucol as therapy for diabetes mellitus and in the application of microencapsulation of pancreatic β- cells. Bile acids improved the stability of the pharmaceutical formulation system containing probucol and enhanced the oral delivery resulting in greater bioavailability, tissue concentrations and glucose lowering effects in diabetic animals. Bile acids also improved the viability and activity of pancreatic β-cells within microcapsules via cellular protective effects.
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ISHII, AKIRA, HIROSHI SENO, HIDEKI HATTORI, TADASHI OGAWA, TAMIE NAKAJIMA, KAZUYA KITAMORI, HISAO NAITO, MINA NOMURA, RINA KANEKO i YUDAI SUZUKI. "Simple and Rapid Quantitation of 21 Bile Acids in Rat Serum and Liver by UPLC-MS-MS: Effect of High Fat Diet on Glycine Conjugates of Rat Bile Acids". Nagoya University School of Medicine, 2013. http://hdl.handle.net/2237/17602.
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Morgan, Sherif. "The Bile Acid, Deoxycholic Acid, Modulates IGF-IR Function in Colon Cancer Cells". Diss., The University of Arizona, 2009. http://hdl.handle.net/10150/194122.
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Deoxycholic acid (DCA) is a secondary bile acid postulated to be involved in the etiology and the progression of colorectal cancer, but its specific mechanisms are not fully understood. DCA has been shown to induce apoptosis allowing selection for apoptosis-resistant cells, which highlights the importance of understanding the mechanisms of action of DCA. Previously, it has been demonstrated that DCA perturbs the plasma membrane, leading to the activation of receptor tyrosine kinases. Because the insulin-like growth factor-1 receptor (IGF-IR), a receptor tyrosine kinase, is demonstrated to play a significant role in protecting colorectal cancer cells from apoptosis, we hypothesized that DCA modulates IGF-IR functions in colorectal cancer cells. We demonstrated that DCA induced the dynamin-dependent endocytosis of IGF-IR through both clathrin-mediated and caveolin-1-dependent mechanisms. Endocytosis of IGF-IR sensitized cells to DCA-induced apoptosis, which demonstrated that IGF-IR played a role in protecting cells against DCA-induced apoptosis. Since DCA-induced endocytosis of IGF-IR was determined to be a caveolin-1 dependent process, caveolin-1 knockdown in HCT116 (HCT116-Cav1-AS) prevented the DCA-mediated endocytosis of IGF-IR. However, we observed an increased sensitivity of DCA-induced apoptosis in the Cav1-AS cells. This suggested that caveolin-1 knockdown altered the plasma membrane dynamics such that although IGF-IR was maintained at the plasma membrane, it facilitated a pro-apoptotic signal. We demonstrated that DCA induced the activation of the pro-apoptotic p38 signaling pathway in HCT116-Cav1-AS, but not in HCT116-Mock, via IGF-IR. Inhibition of both the IGF-IR and p38 independently in HCT116-Cav1-AS significantly decreased their sensitivity to DCA-induced apoptosis. These observations demonstrated that, in a caveolin-1 dependent manner, IGF-IR played a dynamic role in the DCA-mediated apoptosis. Finally, we provided preliminary evidence demonstrating that autophagy played a central role in protecting DCA-resistant cells from DCA-induced apoptosis.Since resistance to DCA also confers apoptosis-resistance, understanding the mechanisms that lead to or prevent DCA-induced cell death is significant, since they can lead to the development of novel therapeutic strategies to sensitize apoptosis-resistant colorectal cancer cells to undergo cell death.
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Gälman, Cecilia. "Modulation of bile acid and cholesterol metabolism in health and disease /". Stockholm ; Karolinska institutet, 2004. http://diss.kib.ki.se/2004/91-7349-948-x.
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PULEO, Gianluigi. "Synthesis and use of bile acid derived organocatalysts". Doctoral thesis, Scuola Normale Superiore, 2009. http://hdl.handle.net/11384/85788.
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The central idea of this work was design, synthesis and study of catalytic activity and enantioselectivity of new organocatalysts containing a chiral cavity mimicking the enzymatic pocket of Aldolase I. Following the longstanding interest of our research group in the use of bile acid derivatives in enantioselective processes, attention was addressed to the development of organocatalysts having bile acid structure, where, because of its concave structure, due to the cis junction of the A and B cyclohexanic rings (Figure 3), the cholestanic backbone and the appended substituents should form a chiral cleft that can help the enantioselection. In addition, the presence of free hydroxyl groups can constitute a further advantage by controlling, via hydrogen bonds, the position of the substrate in the cavity of organocatalyst.
In particular in this project were synthesized:
· A wide class of monoprolinamide derivatives of bile acids, in order to find the right match between proline and cholestanic backbone. In particular synthesis of proline derivatives in different position of bile acid could throw light on the influence of position of proline moiety in the cholestanic emicavity on selectivity of organocatalyst.
· A class of bisprolinamide derivatives of bile acids that could take advantage from the cooperative effect of two proline moieties.
In designing synthesis of these derivatives attention has been paid to the use of low cost, easy and fast procedures in order to improve availability of the new organocatalysts.
Activity and enantioselectivity of this new organocatalysts have been studied with particular attention to:
· Aldol reaction
· Michael reaction
During the activity studies evaluation of parameters that can improve rate of different reaction (temperature, solvents, catalyst loading, reagents…) was considered. The possibility to carry out reactions in water and with very low catalyst loading was checked, in order to evaluate ecosostenibility of the chemical process.
Experimental results were collected and analyzed with the help of conformational and computational studies.
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Cheah, Peh Yean. "The DNA-damaging effect of bile acids and the protective effect of cellulose". Diss., The University of Arizona, 1989. http://hdl.handle.net/10150/184639.
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Colon cancer is the second most common type of cancer in the United States. Its incidence is linked epidemiologically to high levels of bile acids in the feces. Bile acids have been implicated as promotors and cocarcinogens in the etiology of colon cancer and as comutagens and mutagens in bacteria. These observations suggest the hypothesis that bile acids may interact directly with DNA. Using agarose gel electrophoresis we showed that bile acids convert covalently closed circular plasmid DNA to the open circular form, indicating strand breakage. We next treated the single stranded circular DNA of phage M13 with bile acids and found that the transfection efficiency of this DNA declined up to a thousand-fold. The concentrations of bile acids used were of the same magnitude as the fecal bile acid concentrations found in colorectal cancer patients. This inactivation was largely prevented when the bile acids were pretreated with cellulose fiber.
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Glinghammar, Björn. "Toxicological aspects of bile acids and human fecal water on cultered human colon carcinoma cells /". Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4816-x/.
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Münch, Andreas. "Collagenous colitis : The influence of inflammation and bile acids on intestinal barrier function". Doctoral thesis, Linköpings universitet, Gastroenterologi och hepatologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-56291.
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Background and aims: Collagenous colitis (CC) is a diarrheal disorder with an incidence rate of 5-6/100000 inhabitants, affecting mainly middle-aged women. The diagnosis is made by histology of the colonic mucosa. Classical findings are a thickened subepithelial collagenous layer and chronic inflammation in the lamina propria. In inflammatory bowel disease (IBD) the mucosal barrier function is important in pathogenesis. The main purpose of the thesis was therefore to describe the barrier function in CC. The cause of CC is uncertain but the condition seems to be associated with bile acid malabsorption. Increased faecal bile acids are known to induce diarrhea. In functional studies the influence of bile acids on mucosal permeability in biopsies of healthy human individuals and in patients with CC was investigated. Methods and patients: In the first paper a single patient with intractable CC was examined before surgery, with loop-ileostomy and after bowel reconstruction. For the other studies a total of 25 patients with CC were included (20 women, 5 men, mean age 66 years). There were three groups (14 patients in clinical remission without medical treatment, 11 with active disease, and 8 of these again after 6 weeks of budesonide treatment); 17 individuals with normal histology served as controls. Endoscopic biopsies from the sigmoid colon were mounted in modified Ussing chambers and assessed for short-circuit current (Isc), transepithelial resistance (TER), and transmucosal passage of chemically killed E. coli K12 after addition of chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA). The biopsies were further investigated with confocal microscopy to assess bacterial transepithelial passage. Results: Para- and transcellular permeability was increased in active CC, but normalized with histological improvement due to faecal stream diversion. After bowel reconstruction, permeability to CrEDTA and HRP increased again. In CC, bacterial uptake in colonic biopsies was significantly higher in all groups than in controls. Despite significant alleviation of symptoms, budesonide did not normalize the increased bacterial passage. Histology was unchanged after 6 weeks of budesonide treatment. DCA augmented mucosal permeability to CrEDTA in a dose-dependent manner and even such a low dose as 100 μmol/l DCA increased bacterial uptake significantly. The combination of bile acids and E.coli K12 had additive effects on TER. 100 μmol/l CDCA and DCA increased bacterial uptake in biopsies of CC patients in remission 4-fold, but had no additive effect on biopsies from patients with active disease. Furthermore, patients in clinical remission on budesonide treatment showed no bile acidinduced effects on E.coli K12 passage. Conclusion: Collagenous colitis presents with increased para/transcellular permeability and bacterial uptake, irrespective of disease activity or budesonide treatment, signifying an underlying mucosal barrier defect. Faecal stream diversion can normalize the barrier dysfunction, but budesonide does not, despite its beneficial clinical effects which alleviate diarrhea or bowel symptoms. Bile acids in physiological concentrations have the potential to augment bacterial uptake, especially in mucosa from CC patients in remission. Budesonide treatment appears to counteract the bile acid induced mucosal impairment. These detrimental effects of bile acids on mucosal barrier function might facilitate initiation and perpetuation of mucosal inflammation in CC.
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Speight, Richard Alexander. "The role of bile acids and farnesoid X receptor in ileal Crohn's disease". Thesis, University of Newcastle upon Tyne, 2015. http://hdl.handle.net/10443/3078.
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The aetiopathogenesis of Crohn’s disease (CD) is characterised by epithelial barrier dysfunction and immune dysregulation in a genetically susceptible host. Exposure to a western diet, a dysbiosis and bile acid (BA) dysmetabolism have also been implicated. The BA receptor, farnesoid-x receptor (FXR), is central to the crosstalk between the host and its microbiota. FXR acts to maintain the epithelial barrier and has an immuno-modulatory function although the mechanism is not fully understood. The first aim of this study was to investigate the effect of FXR agonism using invitro models of cytokine-induced epithelial barrier dysfunction. Functional and morphological studies of Caco-2 cell monolayers demonstrated that FXR acts to maintain epithelial cell morphology, probably via a mechanism involving the regulation of myosin light chain kinase expression. FXR agonism was also able to abolish the IL-8 response of HT29 cells to stimulation with TNFα. The second aim of this study was to investigate the link between a westernlifestyle diet, impaired BA signalling and ileal inflammation in a mouse model of obesity. Animals fed a western-lifestyle diet expressed more ileal inflammatory cytokine. There was a trend to suggest that supplementation with an FXR agonist reduced inflammatory cytokine expression. Finally, this study aimed to both measure FXR activity in patients with ileal CD, but also to optimise an ex-vivo tissue culture model to assay the effect of FXR agonism on ileal mucosal cytokine production. FXR activity was significantly reduced in patients with ileal CD as compared with controls. An ex-vivo tissue culture model was optimised, but there was no evidence that FXR agonism could attenuate the response of primary tissue to stimulation with inflammatory cytokine. xiv In summary, the data presented support the hypothesis that disrupted bile acid signalling, via FXR, may predispose to the development of ileal CD by impairing gut epithelial immune homeostasis.
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Zhang, Xuejun. "Branched and spiral organic nanotubes based on the self-assembly of bile acids". Master's thesis, University of Central Florida, 2010. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/4542.
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The fluorescent composite tubes can undergo pH switchable spiral/straight, which are a promising system for a variety of materials and biological applications.; The self-assembly of chiral amphiphilic molecules in aqueous solutions is of particular interest because the chirality of individual molecules is often expressed in their supermolecular structures. Self-assembled tubes made of chiral amphiphilic molecules represent useful supramolecular architectures which hold promise as controlled release vehicles for drug delivery, encapsulates for functional molecules, and nanoreactors for chemical reactions. Lithocholic acid (LCA) is a secondary bile acid with the concentration being identical to that of cholesterol in the hepatic bile and gallbladder. It has a rigid, nearly planar hydrophobic steroid nucleus, with four hydrogen atoms and one hydroxyl group directed toward the concave side, and the convex side with three methyl groups. The ionic head with a carboxyl group is linked to the steroid nucleus through a short alkyl chain. In this thesis work, I study the self-assembly behavior of LCA at the liquid-solid interface, in confined spaces, and bulk solution. We find that the initially formed LCA vesicles further assemble into fractal tubes on glass slides by diffusion-limited aggregation and pronglike tubes by the capillary flow generated in an evaporating vesicle solution confined by two parallel glass slides. While in bulk solution, the LCA vesicles linearly aggregate and fuse into spiral tubes at pH 12.0. The spiral tubes can transition into a straight shape as the pH of solution is reduced to 7.4. The shape transition of the tubes is reversible as the pH of solution is adjusted back to 12.0. The pH-switchable shape transition suggests that the self-assembled LCA tubes can act as a supramolecular chemical spring. Finally, the LCA tubes are endowed with optical functionality by embedding cadmium sulfide nanopaticles (CdS) in the tube walls by the co-assembling synthesis of cadmium sulfide (CdS) nanoparticles with lithocholic acid (LCA) molecules.ID: 029051028; System requirements: World Wide Web browser and PDF reader.; Mode of access: World Wide Web.; Thesis (M.S.)--University of Central Florida, 2010.; Includes bibliographical references.
M.S.
Masters
Department of Mechanical, Materials and Aerospace Engineering
Engineering and Computer Science
Materials Science and Engineering
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Lundåsen, Thomas. "Studies on the hormonal regulation of bile acid synthesis /". Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-053-4/.
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Baxter, Debbie Jane. "Molecular mechanisms of biliary lipid secretion". Thesis, Liverpool John Moores University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298908.
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Delsol, Anne Aline Germaine. "Microbial 7-hydroxylation of the steroid lithocholic acid : a novel approach to produce bile acids for gallstone therapy". Thesis, University of Exeter, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297640.
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Castellanos, jankiewicz Ashley. "Bile acids signaling as a novel mechanism in the hypothalamic control of energy balance". Thesis, Bordeaux, 2019. http://www.theses.fr/2019BORD0218.
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Introduction : Les acides biliaires (AB) sont des molécules connues pour digérer les lipides. En activant le récepteur couplé à la protéine G Takeda 5 (TGR5) dans les tissus périphériques, ils peuvent également servir de molécules de signalisation pour réduire le poids corporel et améliorer le profil glycémique. L'activation de TGR5 peut aussi augmenter la dépense énergétique dans le tissu adipeux, mais les voies métaboliques impliquées dans ces effets sont encore mal connues. Ces observations impliquent une action anti-obésité du TGR5. Cependant, toutes les études sur les AB dans la balance énergétique se sont concentrées exclusivement sur des tissus périphériques. Comme le principal centre de convergence des signaux nutritifs, hormonaux et environnementaux se trouve dans le cerveau, et en particulier dans l'hypothalamus, nous avons émis l'hypothèse que l'activité hypothalamique du TGR5 pourrait moduler la balance énergétique, en particulier dans un contexte d’obésité. Objectif : Démontrer la fonction du système AB – TGR5 dans des populations de cellules hypothalamiques connues pour contrôler l’homéostasie énergétique et étudier sa pertinence pour le traitement de l’obésité. Méthodes : Des canules intra-cérébro-ventriculaires (ICV) ont été implantées sur des souris mâles C57Bl6/J minces (sous régime standard) ou obèses (sous régime riche en graisses) pour permettre l'administration pharmacologique aiguë ou chronique des agonistes du TGR5. Des souris TGR5flox/flox ont été utilisées pour provoquer la délétion du récepteur dans l'hypothalamus médio-basal (HMB), par l’injection in situ d’un AAV-Cre. Nous avons mesuré le poids corporel, prise alimentaire, composition corporelle, sensibilité à l'insuline, niveaux des AB hypothalamiques et plasmatiques et dépense énergétique. Pour bloquer la signalisation sympathique, nous avons exposé les souris à un environnement de thermoneutralité (30°C) ou à une sympathectomie chimique. Des marqueurs de la lipolyse, de la thermogenèse ou du métabolisme thyroïdien ont été mesurés dans le foie, le tissu adipeux et l’hypothalamus par qPCR ou western blot. Toutes les études ont été approuvées par le comité d'éthique en expérimentation animale de l'Université de Bordeaux. Résultats : Nous montrons que les transporteurs du TGR5 et des AB s’expriment dans l’HMB et que les souris obèses ont une diminution des AB dans la circulation et l’hypothalamus. L'administration aiguë d'agonistes du TGR5 (ICV ou intra-HMB) réduit la prise alimentaire et le poids corporel chez les souris obèses, tout en améliorant leur sensibilité à l'insuline. De plus, l'administration chronique ICV de l’agoniste réduit le poids corporel et l'adiposité, tout en augmentant la dépense énergétique et les marqueurs de l'activité sympathique dans le tissus adipeux. La thermo-neutralité ainsi que la sympathectomie chimique atténuent ces effets, démontrant que l’activité du récepteur TGR5 nécessite un tonus sympathique accru. La délétion de TGR5 dans le HMB (souris TGR5flox/flox) n'a aucun effet chez les souris minces. Cependant, l’exposition à une nourriture riche en graisse augmente rapidement leur poids, prise alimentaire et adiposité. Lors de l’exposition au froid (4 heures à 4°C), l’expression des marqueurs de lipolyse et thermogenèse dans le tissu adipeux était atténuée, suggérant une interruption de la signalisation sympathique. Enfin, la suppression du TGR5 dans le HMB de souris déjà obèses augmente l'adiposité en induisant une hyperphagie, aggravant l’obésité. Conclusions : Nos résultats prouvent l’existence d’un système fonctionnel du TGR5 hypothalamique, un récepteur des AB. Nous montrons pour la première fois que l'activation du TGR5 dans le HMB induit une myriade d'effets qui améliorent des paramètres métaboliques, et que cela dépend de l'activation du système nerveux sympathique. Ainsi, nous dévoilons un nouveau mécanisme d'action pour des potentiels traitements contre l'obésitéIntroduction: Bile acids (BA) are cholesterol-derived molecules mostly known for their role in digesting lipids. By activating the Takeda G protein coupled receptor 5 (TGR5) in peripheral organs, they can also act as signaling molecules to reduce body weight and improve glucose homeostasis. Notably, TGR5 activation can increase energy expenditure in brown adipocytes, although the metabolic pathways involved in these effects are not yet clear. These outcomes imply an anti-obesity function for TGR5. However, all studies investigating BA in energy balance have exclusively focused on peripheral tissues. Since the major center of convergence of nutrient, hormonal, and environmental cues is the brain, particularly the hypothalamus, we hypothesized a role for TGR5 in this brain structure, suggesting that hypothalamic TGR5 activity may participate in energy balance, specifically under dietinduced obesity. Objective: To demonstrate the function of the BA – TGR5 system in hypothalamic populations known to control energy homeostasis, and disentangle its relevance for the treatment of diet-induced obesity. Methods: C57Bl6/J male mice that were either lean (standard chow) or diet-induced obese (60% high-fat diet; HFD) were implanted with an intra-cerebroventricular (ICV) cannula for the pharmacological delivery of TGR5 agonists. TGR5flox/flox mice were used to target the sitespecific deletion of the receptor within the mediobasal hypothalamus (MBH), through the stereotaxic delivery of AAV-Cre. The following metabolic outputs were measured: body weight, food intake, body composition (EchoMRI analyzer), insulin sensitivity, serum and hypothalamic BA (liquid mass spectrometry), and energy expenditure (TSE Phenomaster system). To block sympathetic signaling, we exposed mice to thermoneutrality (30°C) or performed chemical sympathectomy (6-hydroxydopamine; 80mg/kg i.p.). Markers of lipolysis, thermogenesis, and thyroid metabolism were measured in the liver, adipose and hypothalamic tissues by qPCR or western blots. All studies received the approval from the animal ethical committee of the University of Bordeaux. Results: We demonstrate that TGR5 and BA transporters are expressed in the MBH and that diet-induced obese mice have decreased circulating and hypothalamic BA. Acute ICV or intra-MBH administration of TGR5 agonists reduced food intake and body weight in dietinduced obese mice only, and improved insulin sensitivity. Accordingly, chronic ICV administration of the TGR5 agonist in obese mice reduced their body weight and adiposity, while increasing energy expenditure and mRNA markers of sympathetic activity in the adipose tissue. Indeed, experiments conducted at thermoneutrality or chemical sympathectomy blunted these effects, demonstrating that central TGR5 effects require an enhanced sympathetic tone. By using TGR5flox/flox mice coupled with the delivery of an AAVCre, we observed that the deletion of TGR5 in the MBH had no effect in chow-fed mice. However, a HFD switch rapidly increased their body weight, food intake and adiposity. When exposed to the cold (4 h at 4°C), protein levels of lipolysis and thermogenesis markers in the adipose tissue were blunted, implying an interruption in sympathetic signaling to the periphery due to hypothalamic downregulation of TGR5. Lastly, Cre-dependent deletion of TGR5 in the MBH of already obese mice rapidly increased adiposity by inducing hyperphagia, worsening their obese phenotype. Conclusions: Our work proves the existence of a functional hypothalamic BA – TGR5 receptor system. We show for the first time that the activation of TGR5 in the MBH decreases body weight and adiposity, while increasing energy expenditure through recruitment of the sympathetic nervous system. Taken together, these results expose a new mechanism of action for potential anti-obesity therapies
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Kandell, Risa Lynne. "Bile acid-induced DNA damage and repair in bacterial and mammalian cells". Diss., The University of Arizona, 1990. http://hdl.handle.net/10150/184976.
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Colon cancer is the second most common type of cancer in the United States. Its incidence is linked epidemiologically to high levels of bile acids in the feces. Bile acids have been implicated as promoters and cocarcinogens in the etiology of colon cancer and as comutagens and mutagens in bacteria. These observations suggest the hypothesis that bile acids may damage DNA. By using the DNA-damage inducible SOS system in Escherichia coli, this study shows that when bacteria are exposed to bile acids there is induction of the SOS repair system and preferential survival of cells undergoing repair. Additionally, differential killing assays using repair defective bacteria show strains defective in recombinational repair or excision repair have lower survival when treated with bile acids than their parental wild-type counterparts. Human fibroblasts were treated with bile acids and unscheduled DNA synthesis (UDS) was measured. UDS is considered to represent the DNA synthesis step in excision repair. UDS, measured by autoradiography, was found to significantly increase in human fibroblasts upon treatment with bile acids. In addition, differential cytotoxicity assays with Chinese Hamster Ovary cells showed that different DNA-repair pathway defective cells were sensitive to different bile acids. Introduction of DNA damage and induction of DNA-repair by bile acids implicates them as possible direct carcinogens in the etiology of colon cancer.
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Cheng, Jeffrey Binyan. "CDNA cloning and characterization of enzymes that synthesize bile acids, vitamin D and waxes". Access to abstract only; dissertation is embargoed until after 5/15/2007, 2006. http://www4.utsouthwestern.edu/library/ETD/etdDetails.cfm?etdID=150.
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Adebola, Oluwakemi. "The relationship between probiotics, prebiotics and bile acids and the impact on gut health". Thesis, University of East London, 2009. http://roar.uel.ac.uk/3196/.
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Epidemiological studies show a diet rich in fats and processed meats is often associated with higher levels of secondary bile acids and carcinogens in the gut and increases the risk of colorectal diseases. In recent years the consumption of probiotics and prebiotics has been widely proposed as a strategy to both prevent colorectal disease and generally improve gut health. The present study investigated the role of synbiotic applications of species of Lactobacilli (L. acidophilus NCFM LYO 10, L. acidophilus NCTC 1723, L. reuteri, L. brevis NCIMB 11973 and L. delbrueckii ss bulgaricus NCTC 12712) and prebiotics (inulin, lactulose and lactobionic acid) in bile acid/salt stress and on bile acid metabolism particularly as it affects deconjugation. In addition the study also looked at the effects of prebiotics on xenobiotic induced cytotoxicity/genotoxicity. Preliminary investigations looked at the ability of Lactobacilli cultures to survive the detergent properties of bile acids and utilise prebiotics for growth. Results showed L. acidophilus NCFM LYO 10 was least sensitive to bile acid/salt stress simulating levels found in the gut whilst other cultures showed different levels of growth inhibition with glycine conjugated bile acids being potentially more toxic than its taurine conjugated counterpart. Lactulose was the prebiotic of choice for both L. acidophilus NCFM LYO 10 and L. reuteri with growth comparable to growth in glucose. Small increases in growth were observed for both cultures with lactobionic acid as substrate whereas other cultures could not effectively utilise any of the prebiotics. Following synbiotic applications ofL. reuteri and L. acidophilus NCFM LYO 10 with lactulose or lactobionic acid increases in growth was observed in cholic and taurocholic acid including L. reuteri in taurochenodeoxycholic acid with lactulose as substrate. No growth benefits were observed in the glycine conjugated bile acids. L acidophilus NCTC 1723 deconjugated taurocholic, glycocholic, taurochenodeoxycholic and taurodeoxycholic acid, no deconjugation was observed for other cultures. The presence of prebiotics impacted on BSH activity i.e. whilst 2.83xlO" 2 nmol/min (p<0.01) cholic acid was released with 2% inulin reduced BSH activity was observed in 2% lactulose with 0.66x10" 2 nmol/min cholic acid released. No growth was observed in 2% lactobionic acid. Uncooperative and mixed inhibition kinetics with respect to taurocholic acid substrate was shown with inulin and lactulose (2, 4 and 6%) with a K; of 12 and 10.5% respectively whereas a dose dependent (0 - 2%) increased CGH enzyme kinetics was observed with lactobionic acid. Comparism of L. acidophilus NCFM LYO 10 cytosolic proteome revealed 16 spots whose expressions were either up or down regulated by the presence of cholic or glycocholic acid. 9 PMFS were identified as proteins involved in glycolysis, chaperones, translation, peptidoglycan and amino acid synthesis. In synbiotic applications with lactobionic acid 14 spots showed different levels of expression. Deoxycholic, glycolithocholic, lithocholic acid (0.5mM) and faecal water 50% (v/v) reduced the viability of HT29 cells by 75, 60, 74 and 50% respectively. Addition of prebiotics inulin and lactulose (0.5-2% w/v) resulted in a concentration dependent increase in the viability of cells exposed to deoxycholic acid by 110% and lithocholic acid by 20%. Similarly, cytotoxicity induced by faecal water was significantly (p<0.05) reduced by inulin (2.5%) and lactobionic acid (0.25%) with cell viability increasing by 40% and 20% respectively. Secondary bile acids lithocholic and deoxycholic acid did not induce E. coll PQ 37 SOS response over a range of concentrations (0.25-2mM), however both faecal water (50% v/v)and 4NQO (2jig/ml) induced p-galactosidase activity. Inulin and lactulose at 2.5% significantly reduced the SOSIP of faecal water by 70% and 57% respectively and by 24% and 74.1% for 4NQO. In conclusion, these findings suggest the protective benefits attributed to synbiotic applications in bile acid/salt stress are specific to the nature and type of bile acids with a rather complex physiological response being induced. Prebiotics exerts a concentration dependent impact on BSH activity and might explain the hypocholesterolemic effects attributed to synbiotic applications. It is also interesting to know that the consumption of prebiotic alone particularly inulin may confer beneficial effects beyond those associated with probiotic survival and growth.
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Kaler, Balwant. "The role of bile acids in kidney failure as a result of obstructive jaundice". Thesis, University of East London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264409.
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Miró, Richart Paula. "Hydrogen-Abstraction, Energy Transfer and Exciplex Formation in Photoactive Systems Based on Bile Acids". Doctoral thesis, Universitat Politècnica de València, 2016. http://hdl.handle.net/10251/64084.
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[EN] Bile acids are a family of amphiphilic steroids that play a pivotal role in physiological functions such as elimination of cholesterol or solubilization of lipids. Chemically, they share a steroidal skeleton with an unusual cis fusion between rings A and B, a short lateral chain ending in a carboxylic acid moiety and different number of hydroxyl groups on the alpha-face. Hence, bile acids offer a versatile architecture that can be used to investigate photophysical processes of interest such as hydrogen atom transfer, through-bond energy trasfer, through-bond exciplex formation and DNA photodamage-related reactions.
First, unmodified bile acids have been used to evaluate hydrogen atom trasfer to benzophenone-like triplet carbonyls. Dehydrogenation of bile acids at positions C-3 and/or C-7 by a radical-mediated mechanism from the excited state of benzophenone has been demonstrated. Moreover, synthesized lithocholic acid derivatives including benzophenone or carbazole as donors and a naphthalene, biphenyl or thymine as acceptors have been employed to investigate through-bond energy transfer and exciplex formation processes. Thus, energy transfer from benzophenone to naphthalene or biphenyl and extended through-bond exciplex formation in benzophenone/naphthalene and benzophenone/biphenyl linked systems has been demostrated by laser flash photolysis. Finally, bile acid derivatives incorporating one benzophenone and two thymine units with different degrees of freedom have been prepared to investigate the photochemical formation of oxetanes or thymine dimers. Photosensitized formation of cyclobutane pyrimidine dimers through the generation of a delocalized triplet excited state has been demonstrated in intermolecular systems, while oxetane formation is observed when the degrees of freedom are reduced.[ES] Los ácidos biliares son una familia de esteroides anfifílicos que juegan un papel clave en diferentes funciones fisiológicas tales como la eliminación del colesterol o la solubilización de lípidos. Su estructura química está constituida por un esqueleto esteroideo con una fusión cis poco común entre los anillos A y B, una cadena lateral corta que termina con una función ácida y un número variable de grupos hidroxilo en la cara alfa. Por tanto, los ácidos biliares ofrecen una estructura versátil que puede ser utilizada para investigar procesos fotofísicos de interés como abstracción de hidrógeno, transferencia de energía y formación de exciplejos a larga distancia o reacciones relacionadas con el daño fotoinducido al ADN. En esta Tesis, en primer lugar, los ácidos biliares naturales se han utilizado para evaluar la abstracción de hidrógeno a carbonilos triplete en compuestos derivados de la benzofenona, demostrándose la deshidrogenación de los ácidos biliares en las posiciones C-3 y/o C-7 por un mecanismo radicalario desde el mencionado triplete de la benzofenona. En segundo lugar, se han preparado derivados de ácido litocólico que incluyen los dadores benzofenona o carbazol y los aceptores naftaleno, bifenilo o timina, que a continuación se han utilizado para investigar los procesos de transferencia de energía y formación de exciplejo intramolecular a larga distancia. De hecho, en los sistemas benzofenona/naftaleno y benzofenona/bifenilo, se demostró por fotólisis de destello láser la transferencia de energía desde benzofenona a naftaleno o bifenilo y la formación de exciplejo a larga distancia. Por último, se han preparado derivados de ácidos bliares que incorporan una unidad de benzofenona y dos de timina en diferentes posiciones del esqueleto para investigar la influencia de los diferentes grados de libertad en la formación fotosensibilizada de oxetanos o dímeros de timina. Gracias a ellos, se ha demostrado la formación fotosensibilizada de dímeros ciclobutánicos pirimidínicos a través de la generación de estados excitados triplete deslocalizados en sistemas en los que la benzofenona es intermolecular, mientras que se observa formación de oxetanos cuando los grados de libertad se ven reducidos.
[CAT] Els àcids biliars són una família d'esteroides anfifílics que juguen un paper clau en funcions fisiològiques com l'eliminació del colesterol o la solubilització de lípids. La seua estructura química està constituïda per un esquelet esteroïdal amb una fusió cis entre els anells A i B poc comuna, una cadena lateral curta que acaba amb una funció àcida i un nombre diferent de grups hidroxil en la cara alfa. D'aquesta manera, els àcids biliars ofereixen una estructura versàtil que pot ser utilitzada per investigar processos fotofísics d'interès com abstracció d'hidrogen, transferència d'energia i formació de exciplexes a llarga distància o reaccions relacionades amb el dany a l'ADN induït per llum. En primer lloc, els àcids biliars naturals s'han utilitzat per avaluar la abstracció d'hidrogen a carbonils triplets derivats de la benzofenona, demostrant-se la deshidrogenació dels àcids biliars en les posicions C-3 i/o C-7 per un mecanisme radicalari des de l'estat excitat de la benzofenona. A més, derivats d'àcid litocòlic que inclouen els donadors benzofenona o carbazol i els acceptors naftalé, bifenil o timina s'han utilitzat per investigar els processos de transferència d'energia i formació de exciplexe a llarga distància. En els sistemes benzofenona /naftalé i benzofenona/bifenil la fotòlisis làser va demostrar la transferència d'energia des de benzofenona a naftalé o bifenil i la formació d'exciplexe a llarga distància. Finalment, per tal d'investigar la formació fotosensibilitzada d'oxetans o dímers de timina, s'han preparat derivats d'àcids bliars que incorporen una unitat de benzofenona i dues de timina amb diferents graus de llibertat. La formació fotosensibilitzada de dímers ciclobutànics pirimidínics mitjançant la generació d'estats excitats triplet deslocalitzats ha estat demostrada en sistemes intermoleculars, mentre que la formació d'oxetans s'observa quan els graus de llibertat es veuen reduïts.
Miró Richart, P. (2016). Hydrogen-Abstraction, Energy Transfer and Exciplex Formation in Photoactive Systems Based on Bile Acids [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/64084
TESIS
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Pournaras, Dimitrios. "Mechanisms maintaining reduced appetite and normoglycaemia after metabolic surgery : the role of bile acids". Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/10201.
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Obesity is becoming the healthcare epidemic of this century. Weight loss surgery is the only effective treatment for morbid obesity. Furthermore glycaemic control in type 2 diabetic patients is improved after metabolic surgery. Here I observed that with gastric bypass, type 2 diabetes can be improved and even rapidly put into a state of remission irrespective of weight loss. This is achieved via an improvement of both insulin resistance and insulin production. Reduced insulin resistance within the first week after surgery remains unexplained, but increased insulin production in the first week after surgery may be explained by the enhanced postprandial GLP-1 response. In addition, I demonstrate that bile flow changes lead to increased gut hormone response in animal models. Roux-en-Y gastric bypass in humans causes changes in bile flow leading to increased plasma bile acid concentrations. This phenomenon may explain the improved glycaemic control following gastric bypass. In conclusion I investigated the mechanism of diabetes remission after metabolic surgery and explored the role of gut hormones and bile acids in the changes in glucose homeostasis following metabolic surgery.
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Styles, Nathan Allen. "The characterization of the subcellular localization of bile acid CoA:N-acyltransferase". Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2007p/styles.pdf.
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Han, Shuxin. "Vitamin D receptor regulation of cholesterol 7[alpha]-hydroxylase gene transcription and bile acid synthesis in human hepatocytes". [Kent, Ohio] : Kent State University, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=kent1257459841.
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