Regulation of the rat NHE3 gene promoter by sodium butyrate

Kiela, Pawel R.; Hines, Eric R.; Collins, James F.; Ghishan, Fayez K.

doi:10.1152/ajpgi.2001.281.4.g947

Cited by 46 publications

(39 citation statements)

References 40 publications

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“…Sp3 acetylation stimulates ENaC expression but represses human insulin-like growth factor binding protein-3 expression upon butyrate stimulation (26,37). On the other hand, PKA activation is involved in increased NHE3 expression upon butyrate treatment (16). In butyrate-mediated NHE8 gene expression increased Sp3 binding on the human NHE8 basal promoter region is correlated with the increased Sp3 protein nuclear translocation.…”

Section: Discussionmentioning

confidence: 98%

“…Importantly, NHE-mediated sodium absorption during intestinal maturation is regulated by growth factors (14,30,32) and steroids (8,15,33). Inflammatory cytokine and nutritional factors also play roles in regulating NHE function (1,5,16,27,35).…”

Section: Discussionmentioning

confidence: 99%

“…It is known to regulate intestinal sodium absorption by stimulating ENaC (37) and NHE3 (16,20) and not NHE2, but no study determined whether it would have any effect on NHE8, the latest characterized intestinal NHE. Previous studies showed that NHE3 activity was enhanced in rats fed with 5% pectin-supplemented diet and in butyrate-treated cultured intestinal epithelial cells (17,20).…”

Section: Discussionmentioning

confidence: 99%

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Sodium butyrate stimulates NHE8 expression via its role on activating NHE8 basal promoter activity

McCoy

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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FK. Sodium butyrate stimulates NHE8 expression via its role on activating NHE8 basal promoter activity. Am J Physiol Gastrointest Liver Physiol 309: G500 -G505, 2015. First published July 8, 2015; doi:10.1152/ajpgi.00194.2015.-Butyrate is a major metabolite in colonic lumen. It is produced from bacterial fermentation of dietary fiber. Butyrate has been shown to stimulate electroneutral sodium absorption through its regulation on sodium/hydrogen exchanger 3 (NHE3). Although NHE8, the newest addition of intestinal NHE family, is involved in sodium absorption in the intestinal tract, whether butyrate modulates NHE8 expression in the intestinal epithelial cells is not known. In the current study, we showed that butyrate treatment strongly induced NHE8 protein and NHE8 mRNA expression in human intestinal epithelial cells. Transfection with the human NHE8 promoter reporter constructs showed that butyrate treatment stimulated reporter gene expression at an amount comparable with its stimulation of NHE8 mRNA expression. Interestingly, a similar result was also observed in human NHE8 promoter transfected cells after trichostatin (TSA) treatment. Gel mobility shift assay identified an enhanced Sp3 protein binding on the human NHE8 basal promoter region upon butyrate stimulation. Furthermore, Sp3 acetylation modification is involved in butyrate-mediated NHE8 activation in Caco-2 cells. Our findings suggest that the mechanism of butyrate action on NHE8 expression involves enhanced Sp3 interaction at the basal promoter region of the human NHE8 gene promoter to activate NHE8 gene transcription. Thus butyrate is involved in intestinal regulation of NHE8 resulting enhanced sodium absorption.butyrate; NHE8; intestine; Sp3; acetylation BUTYRATE, A MEMBER OF THE short-chain fatty acid family, is produced in large amounts in the colonic lumen by bacterial fermentation of carbohydrates (7). It is important for mucosal homeostasis by modulating cell differentiation and apoptosis (12, 13). Butyrate is the preferred fuel for the colonic epithelial cells and also has significant effects on maintaining colonic health (22). Studies showed that lack of short-chain fatty acids could result in colonic inflammation, such as seen in diversion colitis (11). Decreased availability of luminal butyrate and/or impaired butyrate metabolism have also been found to contribute to ulcerative colitis and pseudomembranous colitis (10, 25).In the intestine, butyrate stimulates sodium absorption by increasing the activity of the epithelial sodium channel (ENaC) and sodium/hydrogen exchanger 3 (NHE3). Unlike sodium channels, which transport sodium following concentration gradient, NHEs mediate the movement of extracellular Na ϩ into cells in exchange for intracellular H ϩ . Multiple NHE isoforms are identified in the intestinal epithelial cells. NHE1 is located at the basolateral membrane in the intestinal epithelial cell and is involved in intracellular pH regulation and cell volume regulation. NHE2, NHE3, and NHE8 are expressed at the apical membrane in th...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Sodium butyrate stimulates NHE8 expression via its role on activating NHE8 basal promoter activity

McCoy

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Plasmid Constructs-Rat NHE3 promoter constructs were prepared in pGL-3 basic luciferase reporter vector (Promega, Madison, WI) as described earlier (14). Since overexpression of Sp or GATA transcription factors activated promoter-less pGL3-basic but not p␤Gal-basic vector (Clontech, Palo Alto, CA) in transfected cells, transactivation experiments with these factors were performed with NHE3 promoter fragments subcloned into p␤Gal-basic.…”

Section: Methodsmentioning

confidence: 99%

“…An array of factors has been implicated in transcriptional regulation of NHE3 gene expression including glucocorticoid hormones (9, 10), thyroid hormone (11), protein kinase C (12), and sodium butyrate (13,14). Previous studies from our laboratory also suggested that transcriptional regulation is a critical component of maturational changes in intestinal NHE3 activity and gene expression during rat postnatal development (15).…”

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confidence: 97%

Transcriptional Regulation of the Rat NHE3 Gene

Kiela

LeSueur

Collins

et al. 2003

Journal of Biological Chemistry

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Expression of sodium-hydrogen exchanger isoform 3 (NHE3) in the intestinal and renal epithelium plays a critical role in sodium absorption and acid/base homeostasis. To decipher rat NHE3 gene regulation, its cisacting regulatory elements and associated transcription factors were characterized by transient transfection of Caco-2, IEC-6, Qt6, and Drosophila SL2 cells. Deletion and mutational analyses demonstrated that the atypical TATA box located at bp ؊26/؊31 was not necessary for promoter activity, and that a ؊20/؉8-bp fragment represents a functional initiator. Within the 81-bp upstream region, three Sp transcription factor binding sites were critical because their mutation drastically reduced promoter activity. The roles of Sp1 and Sp3 were further demonstrated by electromobility shift assay and by transactivation of the NHE3 promoter in SL2 cells by forced expression of Sp1 and Sp3. Both of these transcription factors were found to act synergistically with GATA-5 bound to a GATA box in exon 1 (؉20/؉23 bp). These studies demonstrate that rat NHE3 promoter is initiator-driven and controlled mainly by Sp1 and Sp3, which functionally interact with GATA-5. This interaction represents a novel regulatory mechanism, which is likely to participate in a gradient of intestinal gene expression along the crypt-villus axis.

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SLC9 Gene Family: Function, Expression, and Regulation

Kiela

2018

Comprehensive Physiology

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The Slc9 family of Na /H exchangers (NHEs) plays a critical role in electroneutral exchange of Na and H in the mammalian intestine as well as other absorptive and secretory epithelia of digestive organs. These transport proteins contribute to the transepithelial Na and water absorption, intracellular pH and cellular volume regulation as well as the electrolyte, acid-base, and fluid volume homeostasis at the systemic level. They also influence the function of other membrane transport mechanisms, affect cellular proliferation and apoptosis as well as cell migration, adherence to the extracellular matrix, and tissue repair. Additionally, they modulate the extracellular milieu to facilitate other nutrient absorption and to regulate the intestinal microbial microenvironment. Na /H exchange is inhibited in selected gastrointestinal diseases, either by intrinsic factors (e.g., bile acids, inflammatory mediators) or infectious agents and associated bacterial toxins. Disrupted NHE activity may contribute not only to local and systemic electrolyte imbalance but also to the disease severity via multiple mechanisms. In this review, we describe the cation proton antiporter superfamily of Na /H exchangers with a particular emphasis on the eight SLC9A isoforms found in the digestive tract, followed by a more integrative description in their roles in each of the digestive organs. We discuss regulatory mechanisms that determine the function of Na /H exchangers as pertinent to the digestive tract, their regulation in pathological states of the digestive organs, and reciprocally, the contribution of dysregulated Na /H exchange to the disease pathogenesis and progression. © 2018 American Physiological Society. Compr Physiol 8:555-583, 2018.

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Regulation of the rat NHE3 gene promoter by sodium butyrate

Cited by 46 publications

References 40 publications

Sodium butyrate stimulates NHE8 expression via its role on activating NHE8 basal promoter activity

Sodium butyrate stimulates NHE8 expression via its role on activating NHE8 basal promoter activity

Transcriptional Regulation of the Rat NHE3 Gene

SLC9 Gene Family: Function, Expression, and Regulation

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