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and PPAR-independent pathways on LLC-PK1-F+ acid-base metabolism
1 Department of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, LA, USA
2 Department of Medicine and Feist-Weiller Cancer Center, Louisiana State University Health Science Center, Shreveport, LA, USA
3 Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: twelbo{at}lsuhsc.edu.
Troglitazone was studied in pH-sensitive LLC-PK1-F+ cells to determine the effect on pHi and glutamine metabolism as well as the role of peroxisome proliferatoractivated receptor (PPAR
)-dependent and PPAR-independent signaling pathways.
Troglitazone induces a dose-dependent cellular acidosis that occurs within 4 minutes and persists over 18h as a result of inhibiting NHE-mediated acid extrusion. Cellular
acidosis was associated with glutamine-dependent augmented [15N]ammonium production and decreased [15N]alanine formation from 15N-labeled glutamine. The shift in glutamine metabolism from alanine to ammoniagenesis appears within 3 hours and is
associated after 18h with both a reduction in assayable ALT activity as well as cellular acidosis. The relative contribution of troglitazone-induced cellular acidosis versus the decrease in assayable ALT activity to alanine production could be demonstrated. The PPAR antagonist bisphenol A diglycide ether (BADGE) reversed both the troglitazoneinduced cellular acidosis and ammoniagenesis but enhanced the troglitazone reduction
of assayable ALT activity; BADGE also blocked troglitazone induction of PPRE-driven firefly luciferase activity. The protein kinase C (PKC)-inhibitor chelerythrine mimics
troglitazone effects while phorbol ester reverses the effects on ammoniagenesis consistent with troglitazone negatively regulating the DAG/PKC/ERK pathway. Although functional PPAR signaling occurs in this cell line, the major troglitazoneinduced acid-base responses appear to be mediated by pathway(s) involving PKC/ERK.
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