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Fenofibrate suppresses intestinal chloride secretion through a PPAR‐independent inhibition of basolateral cAMP‐activated K channels
Author(s) -
Bajwa Poonam J.,
Lee Jimmy W.,
Straus Daniel S.,
Lytle Christian
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a546
Subject(s) - fenofibrate , secretion , chemistry , medicine , endocrinology , intracellular , ussing chamber , secretagogue , pharmacology , biochemistry
Secretory diarrhea remains a major infectious cause of mortality worldwide. We discovered that fenofibrate, a PPARα agonist prescribed widely for hyperlipidemia, dramatically suppressed intestinal Cl − secretion. Oral administration of fenofibrate (0.05% w/w) to mice for 6 days produced a marked inhibition (64% n=6) of cAMP‐induced Cl − secretory current without affecting basal 22 Na + or K + ( 86 Rb + ) absorption by isolated distal colonic mucosae. A similar inhibitory effect was observed in jejunal and colonic mucosae pretreated in the Ussing chamber for just 30 min with 100 μM fenofibrate. The same treatment of cultured T84 cells inhibited cAMP‐induced electrogenic Cl − secretion by 82% (n=6) without affecting Ca 2+ ‐induced Cl − secretion. Experiments on permeabilized T84 cells revealed that fenofibrate inhibits basolateral cAMP‐activated K + current without affecting apical Cl − current. The inhibition persisted up to 6 h after fenofibrate washout and recovered fully after ~24 h. Our results suggest that fenofibrate suppresses intestinal Cl − secretion by a mechanism independent of transcriptional regulation through PPARα. Instead, fenofibrate or its intracellular metabolite fenofibric acid appears to inhibit basolateral K + recycling via KCNQ1/KVLQT channels.