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Departments of Pediatrics and Physiology, Steele Memorial Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona 85724
Short-chain fatty acids, and especially butyrate (NaB),
stimulate sodium and water absorption by inducing colonic
Na+/H+ exchange (NHE). NaB induces NHE3
activity and protein and mRNA expression both in vivo and in vitro.
NaB, as a histone deacetylase (HDAC) inhibitor, regulates gene
transcription. We therefore studied whether NaB regulates transcription
of the rat NHE3 promoter in transiently transfected Caco-2 cells. NaB
(5 mM) strongly stimulated reporter gene activity, and this stimulation
was prevented with actinomycin D, indicating transcriptional
activation. NaB effects on the NHE3 promoter depended on the activity
of Ser/Thr kinases, in particular, protein kinase A (PKA). However, PKA
stimulation alone did not have an effect on promoter activity, and it
did not act synergistically with NaB. Another HDAC inhibitor,
Trichostatin A (TSA), stimulated NHE3 promoter in a Ser/Thr
kinase-independent fashion. The putative NaB-responsive elements were
localized within 
320/34 bp of the NHE3 promoter. These findings
suggest that PKA mediates NaB effects on NHE3 gene transcription and
that the mechanism of NaB action is different from that of TSA.
sodium-hydrogen exchanger; short-chain fatty acids; signal transduction; serine/threonine kinases; protein kinase A
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