Mechanisms of lysophosphatidic acid (LPA) mediated stimulation of intestinal apical Cl−/OH− exchange

Abstract

Lysophosphatidic acid (LPA), a potent bioactive phospholipid, is a natural component of food products like soy and egg yolk. LPA modulates a number of epithelial functions and has been shown to inhibit cholera toxin-induced diarrhea. Antidiarrheal effects of LPA are known to be mediated by inhibiting chloride secretion. However, the effects of LPA on chloride absorption in the mammalian intestine are not known. The present studies examined the effects of LPA on apical Cl−/OH− exchangers known to be involved in chloride absorption in intestinal epithelial cells. Caco-2 cells were treated with LPA, and Cl−/OH− exchange activity was measured as DIDS-sensitive 36Cl− uptake. Cell surface biotinylation studies were performed to evaluate the effect of LPA on cell surface levels of apical Cl−/OH− exchangers, downregulated in adenoma (DRA) (SLC26A3), and putative anion transporter-1 (SLC26A6). Treatment of Caco-2 cells with LPA (100 μM) significantly stimulated Cl−/OH− exchange activity. Specific agonist for LPA2 receptor mimicked the effects of LPA. LPA-mediated stimulation of Cl−/OH− exchange activity was dependent on activation of phosphatidylinositol 3-kinase/Akt signaling pathway. Consistent with the functional activity, LPA treatment resulted in increased levels of DRA on the apical membrane. Our results demonstrate that LPA stimulates apical Cl−/OH− exchange activity and surface levels of DRA in intestinal epithelial cells. This increase in Cl−/OH− exchange may contribute to the antidiarrheal effects of LPA.