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Substrate-induced regulation of the human colonic monocarboxylate transporter, MCT1

Mark A. Cuff, Daniel W. Lambert and Soraya P. Shirazi-Beechey

Butyrate is the principal source of energy for colonic epithelial cells, and has profound effects on their proliferation, differentiation and apoptosis. Transport of butyrate across the colonocyte luminal membrane is mediated by the monocarboxylate transporter 1 (MCT1). We have examined the regulation of expression of human colonic MCT1 by butyrate, in cultured colonic epithelial cells (AA/C1). Treatment with sodium butyrate (NaBut) resulted in a concentration- and time-dependent upregulation of both MCT1 mRNA and protein. At 2 mM butyrate, the magnitude of induction of mRNA (5.7-fold) entirely accounted for the 5.2-fold increase in protein abundance, and was mediated by both activation of transcription and enhanced mRNA stability. The other monocarboxylates found naturally in the colon, acetate and propionate, had no effect. The properties of butyrate uptake by AA/C1 cells were characteristic of MCT1. Induction of the MCT1 protein resulted in a corresponding increase in the maximal rate of butyrate transport. The V_max for uptake of [U-¹⁴C]butyrate was increased 5-fold following pre-incubation with 2 mM NaBut, with no significant change in the apparent K_m. In conclusion, this study is the first to show substrate-induced regulation of human colonic MCT1. The basis of this regulation is a butyrate-induced increase in MCT1 mRNA abundance, resulting from the dual control of MCT1 gene transcription and stability of the MCT1 transcript. We suggest that butyrate-induced increases in the expression and resulting activity of MCT1 serve as a mechanism to maximise intracellular availability of butyrate, to act both as a source of energy and to influence processes maintaining cellular homeostasis in the colonic epithelium.

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