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The thiazolidinedione (TZD) drugs rosiglitazone (Ro) and pioglitazone (Po) are PPAR-y agonists in widespread clinical use as insulin-sensitizing agents in Type 2 diabetes. On the basis of recent evidence implicating PPAR-γ as a positive modulator of intestinal epithelial differentiation, we hypothesized that TZD drugs might attenuate intestinal secretory function. To evaluate this possibility, we examined the effects of Ro and Po on electrogenic Cl- secretion [short-circuit current (Isc)] in mouse intestinal segments and in cultured human intestinal epithelial cells (HT29-Cl.19A). As hypothesized, oral administration of Ro (20 mg·kg-1·day-1) to mice for 8 days markedly reduced intestinal Isc responses to cAMP (forskolin)- and Ca2+ (carbachol)-dependent stimuli. In these Ro-treated mice, cholera toxin-induced intestinal fluid accumulation was reduced 65%. With continued Ro treatment, the Isc response to carbachol recovered significantly, whereas that to forskolin remained attenuated. Treatment of HT29 cells for 5 days with 10 μM Ro or Po in vitro brought about a similar hyposecretory state. In HT29 cells, the loss of cAMP-dependent Cl- secretion was attributable to a reduced expression of CFTR Cl- channel, KCNQ1 K+ channel, and Na-K-2Cl cotransporter-1 proteins. The transient loss of Ca2+-dependent Cl- secretion involved an impairment of basolateral Ca2+-stimulated K+ channel activity without a detectable loss of KCa3.1 channel protein. Our results establish TZD drugs as important modulators of intestinal Cl- secretory function. [ABSTRACT FROM AUTHOR]

Fibrates are peroxisome proliferator- activated receptor-α (PPARα) 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 (Isc) 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 Isc 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 Isc with an IC50 ∼1 μM. whereas other PPARα 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. [ABSTRACT FROM AUTHOR]