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.
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