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You searched for subject:(Bile acid signaling). Showing records 1 – 3 of 3 total matches.

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University of Arizona

1. Jean-Louis, Samira. Membrane Perturbation By Bile Acids and Their Potential Role in Signaling .

Degree: 2005, University of Arizona

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. Advisors/Committee Members: Martinez, Jesse D (advisor), Wilson, Jean (committeemember), Nelson, Mark (committeemember), Payne, Claire (committeemember), Meuillet, Emmanuelle (committeemember), Erickson, Robert (committeemember).

Subjects/Keywords: Bile Acid; DCA; Membrane Perturbation; Cholesterol; EGFR; Signaling

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APA (6th Edition):

Jean-Louis, S. (2005). Membrane Perturbation By Bile Acids and Their Potential Role in Signaling . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/193551

Chicago Manual of Style (16th Edition):

Jean-Louis, Samira. “Membrane Perturbation By Bile Acids and Their Potential Role in Signaling .” 2005. Doctoral Dissertation, University of Arizona. Accessed August 21, 2019. http://hdl.handle.net/10150/193551.

MLA Handbook (7th Edition):

Jean-Louis, Samira. “Membrane Perturbation By Bile Acids and Their Potential Role in Signaling .” 2005. Web. 21 Aug 2019.

Vancouver:

Jean-Louis S. Membrane Perturbation By Bile Acids and Their Potential Role in Signaling . [Internet] [Doctoral dissertation]. University of Arizona; 2005. [cited 2019 Aug 21]. Available from: http://hdl.handle.net/10150/193551.

Council of Science Editors:

Jean-Louis S. Membrane Perturbation By Bile Acids and Their Potential Role in Signaling . [Doctoral Dissertation]. University of Arizona; 2005. Available from: http://hdl.handle.net/10150/193551


University of Illinois – Urbana-Champaign

2. Fang, Sungsoon. The roles of orphan nuclear receptors, SHP and FXR, and their cofactors in bile acid signaling.

Degree: PhD, Molecular & Integrative Physiology, 2008, University of Illinois – Urbana-Champaign

Bile acids, the end-product of cholesterol catabolism, are important for absorption and solubilization of lipids in the intestine because of their detergent properties. In addition to their roles as detergents, previous studies have revealed that bile acids function as signaling molecules in metabolic pathways such as glucose and fatty acid metabolism as well as cholesterol/bile acid homeostasis. Furthermore, many reports have shown that bile acid signaling finely regulates numerous metabolically relevant genes at the level of their transcription. However, the molecular mechanisms of bile acid signaling to control transcription of genes are poorly understood. In recent years, two orphan nuclear receptors, farnesoid X receptor (FXR) and small heterodimer partner (SHP), have been identified as key regulators in bile acid signaling. FXR was revealed as the first in vivo bile acid biosensor and was shown to regulate cholesterol/bile acid homeostasis by suppressing the transcription of cholesterol 7-a hydroxylase (CYP7A1), the first and rate-limiting enzyme in bile acid biosynthesis. The discovery of the bile acid receptor FXR provided a better understanding of the potential roles of orphan nuclear receptors in transcriptional regulation by bile acids. Consecutive reports showed that bile acid-activated FXR suppressed CYP7A1 gene transcription by inducing another orphan nuclear receptor, small heterodimer partner (SHP), that plays a key role in the negative feedback regulation of bile acid synthesis. Later then, our group showed that bile acid-induced SHP actively recruits the mSin3A/HDAC corepressors and the Swi/SNF chromatin remodeling complex, containing Brm as a central ATPase, to the promoter and suppresses the transcription of the CYP7A1 gene. In order to delineate the repression mechanism of CYP7A1 mediated by SHP, I examined whether histone modifications are also involved in CYP7A1 repression by SHP and whether a functional interplay between chromatin modifying enzymes occurs during the repression of the CYP7A1 gene. Recently, I reported that histone methyltransferase G9a is present in a SHP complex and enhances SHP inhibitory activity to suppress CYP7A1 expression. Besides cholesterol/bile acid homeostasis, FXR and SHP are involved in other metabolic pathways such as glucose homeostasis and fatty acid metabolism through bile acid signaling. Interestingly, it has been reported that the expression level of SHP was strikingly elevated in the liver of obese mice compared to normal mice. Also, it was reported that SHP-transgenic mice have significant features of fatty liver, such as lipid accumulation and elevated levels of hepatic triglycerides. These findings led me to ask how FXR enhances the level of SHP in the liver of obese mice without bile acid signaling. My recent findings suggest that histone acetyltransferase p300 is a critical FXR coactivator for SHP induction by acetylating core histones in response to bile acid treatment in normal mice. However, even without bile acid treatment,… Advisors/Committee Members: Kemper, Byron W. (advisor), Kemper, Jongsook K. (Committee Chair), Katzenellenbogen, Benita S. (committee member), Nardulli, Ann M. (committee member), Bagchi, Milan K. (committee member), Mizzen, Craig A. (committee member).

Subjects/Keywords: Bile acids; Bile acid signaling; Farnesoid X receptor (FXR); Small heterodimer partner (SHP)

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APA (6th Edition):

Fang, S. (2008). The roles of orphan nuclear receptors, SHP and FXR, and their cofactors in bile acid signaling. (Doctoral Dissertation). University of Illinois – Urbana-Champaign. Retrieved from http://hdl.handle.net/2142/47090

Chicago Manual of Style (16th Edition):

Fang, Sungsoon. “The roles of orphan nuclear receptors, SHP and FXR, and their cofactors in bile acid signaling.” 2008. Doctoral Dissertation, University of Illinois – Urbana-Champaign. Accessed August 21, 2019. http://hdl.handle.net/2142/47090.

MLA Handbook (7th Edition):

Fang, Sungsoon. “The roles of orphan nuclear receptors, SHP and FXR, and their cofactors in bile acid signaling.” 2008. Web. 21 Aug 2019.

Vancouver:

Fang S. The roles of orphan nuclear receptors, SHP and FXR, and their cofactors in bile acid signaling. [Internet] [Doctoral dissertation]. University of Illinois – Urbana-Champaign; 2008. [cited 2019 Aug 21]. Available from: http://hdl.handle.net/2142/47090.

Council of Science Editors:

Fang S. The roles of orphan nuclear receptors, SHP and FXR, and their cofactors in bile acid signaling. [Doctoral Dissertation]. University of Illinois – Urbana-Champaign; 2008. Available from: http://hdl.handle.net/2142/47090


University of Rochester

3. Ghatak, Sayak; Redmond, Eileen M. GERD to Barrett’s: dissecting the initial assault.

Degree: PhD, 2014, University of Rochester

Background: Esophageal Adenocarcinoma (EAC) affects about 18000 of the US population with annual mortality around 15000. Barrett’s esophagus (BE) is the single most important risk factor for the development of esophageal adenocarcinoma. The pathogenesis of BE is believed to be driven by protracted reflux of gastric and duodenal contents into the lower esophagus through an incompetent lower esophageal sphincter (LES) in patients with gastro-esophageal reflux disease (GERD), and as a result the esophageal stem cells are transcommitted to a columnar phenotype in the presence of the reflux environment. Bile acids, along with gastric acid at pH 2-4, are the chief components of reflux. </br> Methods: We compared expression of squamous differentiation markers in biopsies taken from normal squamous esophagus and BE. We also treated primary esophageal cells in monolayer culture with bile acid cocktail and looked at the differentially expressed genes compared to control. In order to simulate gastro-esophageal reflux in vitro we developed a 3-D transwell culture model to grow primary esophageal cells in stratified culture. Subsequently, we used this model to demonstrate the morphological and molecular effects of simulated reflux condition on this stratified epithelium in vitro. </br> Results: Our data indicate that a combination of bile acid and gastric acid at pH5 reduces squamous differentiation in primary esophageal cells as an initial step in EGFR-mediated dedifferentiation that enables mucosal repair in response to reflux injury. We have attributed the observed squamous dedifferentiation to the unionized unconjugated and thus intracellular bile acid pool. Our data demonstrate that bile acid at pH5, but not either alone, disrupts tight junction complexes and causes increased permeability of stratified squamous esophageal epithelium. These changes approximate the appearance of dilated intercellular spaces (DIS) similar to that found in GERD patients. These findings provide novel insights into the molecular mechanisms underlying the adaptive responses of the esophageal epithelium to reflux-mediated injury. </br> Conclusion: To extend the relevance of this study in the clinical setting, acid suppression therapy likely will not prevent DIS formation and subsequent initiation of inflammatory response in esophageal epithelium as long as the patient is refluxing bile salts at a less acidic pH. In the majority of clinical situations, long term acid suppression in patients with GERD raises the gastric pH to 4-6. This facilitates the burgeoning of intestinal microflora and increases bacterial deconjugation of bile acid, causing the predominance of unconjugated bile acid refluxing into the esophagus at a pH around 5. Taking parallels from the in vitro results shown in this dissertation, we can conclude that the refluxing cocktail thus formed might be putting patients at risk to bile acid induced altered cellular differentiation.

Subjects/Keywords: 3-D trasnwell culture; Barrett's esophagus; Bile acid; Esophageal cancer; Gastroesophageal reflux disease; Signaling pathway; Esophageal adenocarcinoma; Reflux; 3-D culture; Transwell culture; Human primary cell culture; EGFR; Wnt; Bile acide receptors; Ionization

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Ghatak, Sayak; Redmond, E. M. (2014). GERD to Barrett’s: dissecting the initial assault. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/28858

Chicago Manual of Style (16th Edition):

Ghatak, Sayak; Redmond, Eileen M. “GERD to Barrett’s: dissecting the initial assault.” 2014. Doctoral Dissertation, University of Rochester. Accessed August 21, 2019. http://hdl.handle.net/1802/28858.

MLA Handbook (7th Edition):

Ghatak, Sayak; Redmond, Eileen M. “GERD to Barrett’s: dissecting the initial assault.” 2014. Web. 21 Aug 2019.

Vancouver:

Ghatak, Sayak; Redmond EM. GERD to Barrett’s: dissecting the initial assault. [Internet] [Doctoral dissertation]. University of Rochester; 2014. [cited 2019 Aug 21]. Available from: http://hdl.handle.net/1802/28858.

Council of Science Editors:

Ghatak, Sayak; Redmond EM. GERD to Barrett’s: dissecting the initial assault. [Doctoral Dissertation]. University of Rochester; 2014. Available from: http://hdl.handle.net/1802/28858

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