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MUCOSAL BIOLOGY

Fenofibrate inhibits intestinal Cl^– secretion by blocking basolateral KCNQ1 K⁺ channels

¹Division of Biomedical Sciences, University of California, Riverside; and Department of Anesthesiology, Division of Molecular Medicine, ²David Geffen School of Medicine, University of California, Los Angeles, California

Submitted 23 May 2007 ; accepted in final form 26 September 2007

Fibrates are peroxisome proliferator-activated receptor- (PPAR) ligands in widespread clinical use to lower plasma triglyceride levels. We investigated the effect of fenofibrate and clofibrate on ion transport in mouse intestine and in human T84 colonic adenocarcinoma cells through the use of short-circuit current (I_sc) and ion flux analysis. In mice, oral administration of fenofibrate produced a persistent inhibition of cAMP-stimulated electrogenic Cl^– secretion by isolated jejunum and colon without affecting electroneutral fluxes of ²²Na⁺ or ⁸⁶Rb⁺ (K⁺) across unstimulated colonic mucosa. When applied acutely to isolated mouse intestinal mucosa, 100 µM fenofibrate inhibited cAMP-stimulated I_sc within 5 min. In T84 cells, fenofibrate rapidly inhibited 80% the Cl^– secretory responses to forskolin (cAMP) and to heat stable enterotoxin STa (cGMP) without affecting the response to carbachol (Ca²⁺). Both fenofibrate and clofibrate inhibited cAMP-stimulated I_sc with an IC₅₀ 1 µM, whereas other PPAR activators (gemfibrozil and Wy-14,643) were without effect. Membrane permeabilization experiments on T84 cells indicated that fenofibrate inhibits basolateral cAMP-stimulated K⁺ channels (putatively KCNQ1/KCNE3) without affecting Ca²⁺-stimulated K⁺ channel activity, whereas clofibrate inhibits both K⁺ pathways. Fenofibrate had no effect on apical cAMP-stimulated Cl^– channel activity. Patch-clamp analysis of HEK-293T cells confirmed that 100 µM fenofibrate rapidly inhibits K⁺ currents associated with ectopic expression of human KCNQ1 with or without the KCNE3 β-subunit. We conclude that fenofibrate inhibits intestinal cAMP-stimulated Cl^– secretion through a nongenomic mechanism that involves a selective inhibition of basolateral KCNQ1/KCNE3 channel complexes. Our findings raise the prospect of fenofibrate as a safe and effective antidiarrheal agent.

clofibrate; peroxisome proliferator-activated receptor-; K_v7.1; K_vLQT1; KCNE3; MiRP2; secretory diarrhea; mouse intestine; human T84 cells; antidiarrheal agents