c-Fos Is a Critical Mediator of Inflammatory-Mediated Repression of the Apical Sodium-Dependent Bile Acid Transporter

Neimark, Ezequiel; Chen, Fanglin; Li, Xiaoping; Magid, Margret S.; Alasio, Teresa M.; Frankenberg, Tamara; Sinha, Jyoti; Dawson, Paul A.; Shneider, Benjamin L.

doi:10.1053/j.gastro.2006.05.002

Cited by 45 publications

(39 citation statements)

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“…Furthermore, the inducible transcriptional complex AP-1, composed of c-fos and c-jun proteins, plays a fundamental role in inflammation-controlled ASBT activity [25]. Human, rat and mouse ASBT is inhibited by inflammatory cytokines via direct interactions of c-fos with the ASBT promoter [27]. The activity of this promoter is enhanced by c-jun and repressed by c-fos [27].…”

Section: Introductionmentioning

confidence: 99%

“…Human, rat and mouse ASBT is inhibited by inflammatory cytokines via direct interactions of c-fos with the ASBT promoter [27]. The activity of this promoter is enhanced by c-jun and repressed by c-fos [27]. As subclinical inflammation could be a potentially important mechanism for the low ASBT transporter activity in some gallstone carriers, we focused our investigations on a possible link between inflammatory mediators and ASBT in the ileum of gallstone patients.…”

Section: Introductionmentioning

confidence: 99%

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Diminished Expression of Apical Sodium-Dependent Bile Acid Transporter in Gallstone Disease Is Independent of Ileal Inflammation

et al. 2008

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Background: Non-obese gallstone patients exhibit a diminished expression of apical sodium-dependent bile acid transporter (ASBT) in terminal ileum. Crohn’s ileitis demonstrates a significant downregulation of this transporter. Aim: To test whether subclinical ileal inflammation contributes to gallstone disease. Methods: Biopsies from terminal ileum of female subjects with gallstone disease (n = 7), active Crohn’s disease (n = 17) and controls (n = 22) were investigated. mRNA expression of ASBT, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-8, c-jun and c-fos was measured. c-jun and c-fos protein levels were determined and hematoxylin and eosin staining was applied for ileal histology. Results: ASBT expression was comparably low both in gallstone (47% of controls, p = 0.0093) and Crohn’s disease (42% of controls, p = 0.0008). In gallstone disease there was a non-significant trend towards elevated TNF-α and IL-1β, but all cytokines were increased in active Crohn’s disease. c-jun and c-fos were slightly diminished in patients with gallstones. Neither cytokines nor transcription factors correlated significantly with ASBT. The gallstone-associated ileal biopsies exhibited no histological inflammation. Conclusion: Although the expression of ASBT was similarly diminished in both gallstone and Crohn’s disease, subclinical ileal inflammation does not appear to be relevant in gallstone patients. The mechanisms of transcriptional repression of ASBT in both diseases are apparently different.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Diminished Expression of Apical Sodium-Dependent Bile Acid Transporter in Gallstone Disease Is Independent of Ileal Inflammation

et al. 2008

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“…It has been shown that the protein levels of this transporter are lower in patients with CD than in control individuals (Jung et al, 2004). It has been proposed that ASBT mRNA levels are decreased by proinflammatory cytokines via a mechanism that involves the c-Fos transcription factor in human, rat, and mouse intestinal epithelium (Neimark et al, 2006). In addition, the expression and function of another SLC superfamily member, serotonin transporter (SERT) (gene symbol SLC6A4), is affected by 2,4,6-trinitrobenzenesulfonic acid-induced inflammation in mice (Linden et al, 2005).…”

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confidence: 99%

Changes in mRNA Expression Levels of Solute Carrier Transporters in Inflammatory Bowel Disease Patients

Wojtal¹,

Eloranta²,

Hrúz³

et al. 2009

Drug Metab Dispos

142

111

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ABSTRACT:Inflammatory bowel disease (IBD) is an inflammatory condition that affects the gastrointestinal tract. The solute carrier (SLC) superfamily of transporters comprise proteins involved in the uptake of drugs, hormones, and other biologically active compounds. The purpose of this study was to determine the mRNA expression levels of 15 solute carrier transporters in two regions of the intestine in IBD patients. Endoscopic biopsy specimens were taken from two locations (terminal ileum and colon) for histological examination and RNA extraction. We quantitatively measured the mRNA expression of 15 SLC transporters in 107 IBD patients (53 with Crohn's disease and 54 with ulcerative colitis) and 23 control subjects. mRNA expression was evaluated using the quantitative reverse transcription-polymerase chain reaction technique. We observed that in the ileum of IBD patients, mRNA levels for serotonin transporter, equilibrative nucleoside transporter (ENT) 1, ENT2, and organic anion-transporting polypeptide (OATP) 2B1 were significantly elevated, whereas levels for apical sodium-dependent bile acid transporter (ASBT) and organic zwitterion/cation transporter (OCTN) 2 were significantly lower. In colon, mRNA levels for ENT1, ENT2, concentrative nucleoside transporter (CNT) 2, OATP2B1, and OATP4A1 were significantly higher, whereas mRNA levels for OCTN2 were significantly decreased. In inflamed colon of IBD patients the mRNA expression levels of ENT1, ENT2, CNT2, OATP2B1, OATP4A1, and peptide transporter 1 were significantly higher. We conclude that intestinal SLC mRNA levels are dysregulated in IBD patients, which may be linked to the inflammation of the tissue and provides an indication about the role of inflammatory signaling in regulation of SLC expression.

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“…Diabetes mellitus is characterized by hormonal dysregulation, typically insulin imbalance. Previous studies have shown that ASBT function and expression are regulated by hormones such as glucocorticoids (10,14,30). Whether insulin modulates ASBT expression via a mechanism that influences ASBT expression in diabetes mellitus is not known.…”

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Ileal apical Na⁺-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin

Annaba

Kumar

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin. Am J Physiol Gastrointest Liver Physiol 299: G898 -G906, 2010. First published July 22, 2010; doi:10.1152/ajpgi.00139.2010.-Increased intestinal bile acid absorption and expansion of the bile acid pool has been implicated in the hypercholesterolemia associated with diabetes mellitus. However, the molecular basis of the increase in bile acid absorption in diabetes mellitus is not fully understood. The ileal apical Na ϩ -dependent bile acid transporter (ASBT) is primarily responsible for active reabsorption of the majority of bile acids. Current studies were designed to investigate the modulation of ASBT function and expression in streptozotocin (STZ)-induced diabetes mellitus in rats and to examine the effect of insulin on rat ASBT promoter by insulin. Diabetes mellitus was induced in Sprague-Dawley rats by intraperitoneal injection of low doses of STZ (20 mg/kg body wt) on five consecutive days. Human insulin (10 U/day) was given to a group of diabetic rats for 3 days before euthanasia. RNA and protein were extracted from mucosa isolated from the small intestine and ASBT expression was assessed by real-time quantitative RT-PCR and Western blotting. Our data showed that ASBT mRNA and protein expression were significantly elevated in diabetic rats. Insulin treatment of diabetic rats reversed the increase in ASBT protein expression to control levels. Consistently, ileal Na ϩ -dependent [ 3 H]taurocholic uptake in isolated intestinal epithelial cells was significantly increased in diabetic rats. In vitro studies utilizing intestinal epithelial Caco-2 cells demonstrated that ASBT expression and promoter activity were significantly decreased by insulin. These studies demonstrated that insulin directly influences ASBT expression and promoter activity and that ASBT function and expression are increased in rats with STZinduced diabetes mellitus. The increase in ASBT expression may contribute to disturbances in cholesterol homeostasis associated with diabetes mellitus. hypercholesterolemia; insulinopenia; enterohepatic circulation DIABETES MELLITUS IS A COMPLEX disorder resulting from insulin imbalance and characterized by dyslipidemia and hypercholesterolemia (18,34

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c-Fos Is a Critical Mediator of Inflammatory-Mediated Repression of the Apical Sodium-Dependent Bile Acid Transporter

Cited by 45 publications

References 49 publications

Diminished Expression of Apical Sodium-Dependent Bile Acid Transporter in Gallstone Disease Is Independent of Ileal Inflammation

Diminished Expression of Apical Sodium-Dependent Bile Acid Transporter in Gallstone Disease Is Independent of Ileal Inflammation

Changes in mRNA Expression Levels of Solute Carrier Transporters in Inflammatory Bowel Disease Patients

Ileal apical Na⁺-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin

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c-Fos Is a Critical Mediator of Inflammatory-Mediated Repression of the Apical Sodium-Dependent Bile Acid Transporter

Cited by 45 publications

References 49 publications

Diminished Expression of Apical Sodium-Dependent Bile Acid Transporter in Gallstone Disease Is Independent of Ileal Inflammation

Diminished Expression of Apical Sodium-Dependent Bile Acid Transporter in Gallstone Disease Is Independent of Ileal Inflammation

Changes in mRNA Expression Levels of Solute Carrier Transporters in Inflammatory Bowel Disease Patients

Ileal apical Na+-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin

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Ileal apical Na⁺-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin