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Reprint requests Address requests for reprints to: C. Chris Yun, PhD, Division of Digestive Diseases, Emory University School of Medicine, Whitehead Building, Room 201, 615 Michael Street, Atlanta, Georgia 30322. ccyun@emory.edu.

Drs Lin and Yeruva contributed equally to this work.

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Research Funding:

National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK

Funding This work was funded by National Institutes of Health grants DK061416 (CCY), MH51699 and HD50685 (JC) and by DFG SFB621-C9 (US). SL was supported by the Crohn’s and Colitis Foundation of America. PH was supported by the American Heart Association. AS and MC were supported by postdoctoral stipends of the Hannover biomedical Research School that were funded by the DAAD and Abbot GmbH via the “matching fund” program. We thank the Emory Digestive Disease Research Development Center (supported by DK064399) for the use of light microscope and the Zeiss 510 confocal microscope and the Volkswagen Stiftung for funding of the Leica LSM.

Lysophosphatidic Acid Stimulates the Intestinal Brush Border Na+/H+ Exchanger 3 and Fluid Absorption via LPA5 and NHERF2

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Journal Title:

Gastroenterology

Volume:

Volume 138, Number 2

Publisher:

, Pages 649-658

Type of Work:

Article | Post-print: After Peer Review

Abstract:

BACKGROUND & AIMS Diarrhea results from reduced net fluid and salt absorption caused by an imbalance in intestinal absorption and secretion. The bulk of sodium and water absorption in the intestine is mediated by Na+/H+ exchanger 3 (NHE3), located in the luminal membrane of enterocytes. We investigated the effect of lysophosphatidic acid (LPA) on Na+/H+ exchanger activity and Na+-dependent fluid absorption in the intestine. METHODS We analyzed the effects of LPA on fluid absorption in intestines of wild-type mice and mice deficient in Na+/H+ exchanger regulatory factor 2 (NHERF2; Nherf2−/−)or LPA2 (Lpa2−/−). Roles of LPA5 and NHERF2 were determined by analysis of heterologous expression. RESULTS Under basal conditions, LPA increased fluid absorption in an NHE3-dependent manner and restored the net fluid loss in a mouse model of acute diarrhea. Expression of the LPA receptor LPA5 was necessary for LPA-induced stimulation of NHE3 activity in colonic epithelial cells. Stimulation of NHE3 by the LPA-LPA5 signaling required coexpression of NHERF2, which interacted with LPA5. LPA-mediated intestinal fluid absorption was impaired in Nherf2−/− mice, demonstrating the requirement for NHERF2 in LPA5 activity. However, fluid absorption was unaltered in Lpa2−/− mice. LPA stimulated NHE3 and fluid absorption in part by increasing NHE3 protein abundance at the brush border membrane of intestinal epithelial cells. CONCLUSIONS LPA is a potent stimulant of NHE3 and fluid absorption in the intestine, signaling through LPA5. Regulation by LPA5 depends on its interaction with NHERF2. LPA might be useful in the treatment of certain diarrheal diseases.

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© 2010 by the AGA Institute

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