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Protein Kinase C Is Required for Oleic Acid-Induced Secretion of Glucagon-Like Peptide-1 by Intestinal Endocrine L Cells

Departments of Physiology (R.I., A.I., A.Y., P.L.B.) and Medicine (C.I.W., P.L.B.), University of Toronto, Toronto, Ontario, Canada M5S 1A8; and Department of Internal Medicine I (R.I.), Merheim Medical Center, D-51109 Cologne, Germany

Address all correspondence and requests for reprints to: Dr. P. L. Brubaker, Room 3366 Medical Sciences Building, University of Toronto, 1 King’s College Circle, Toronto, Ontario, Canada M5S 1A8. E-mail: p.brubaker{at}utoronto.ca.

Long-chain, monounsaturated fatty acids (FAs) stimulate secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1) from the intestinal L cell. Because the atypical protein kinase C (PKC), PKC, is involved in FA signaling in many cells, the role of PKC in FA-induced GLP-1 secretion was investigated, using the murine GLUTag L cell line and primary rat intestinal L cells. GLUTag cells expressed mRNA for several PKC isoforms, including PKC, and PKC protein was localized throughout the cytoplasm in GLUTag and primary L cells as well as normal mouse and rat L cells. Treatment with oleic acid (150–1000 µM) for 2 h increased GLP-1 secretion (P < 0.001), and this was abrogated by the PKC inhibitor ZI (P < 0.05) and PKC small interfering RNA transfection (P < 0.05) but not inhibition of classical/novel PKC isoforms. Although most PKC was localized in the particulate compartment of GLUTag cells, oleate treatment did not alter PKC levels or activity in this cell fraction. GLUTag cells expressed mRNA for the Gq-coupled FA receptor GPR120; however, oleic acid did not induce any changes in Akt, MAPK, or calcium, and pretreatment with LY294002 and PD98059 to inhibit phosphatidylinositol 3-kinase and MAPK, respectively, did not prevent the effects of oleic acid. Finally, GLUTag cells also released GLP-1 in response to arachidonic acid (P < 0.001) but were not affected by other long-chain FAs. These findings demonstrate that PKC is required for oleic acid-induced GLP-1 secretion. This enzyme may therefore serve as a therapeutic target to enhance GLP-1 release in type 2 diabetes.

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