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Diacylglycerol kinase inhibitor R59022 attenuates conjugated linoleic acid-mediated inflammation in human adipocytes.

Abstract
Diacylglycerol kinases (DGK) convert diacylglycerol to phosphatidic acid, which has been reported to stimulate calcium release from the endoplasmic reticulum. Based on our published data showing that trans-10, cis-12 conjugated linoleic acid (t10,c12 CLA)-mediated intracellular calcium accumulation is linked to inflammation and insulin resistance, we hypothesized that inhibiting DGKs with R59022 would prevent t10,c12 CLA-mediated inflammatory signaling and insulin resistance in human adipocytes. Consistent with our hypothesis, R59022 attenuated t10,c12 CLA-mediated i) increased gene expression and protein secretion of interleukin (IL)-8, IL-6, and monocyte chemoattractant protein-1 (MCP-1); ii) increased activation of extracellular signal-related kinase (ERK), cJun-NH2-terminal kinase (JNK), and cJun; iii) increased intracellular calcium levels; iv) suppressed mRNA or protein levels of peroxisome proliferator activated receptor γ, adiponectin, and insulin-dependent glucose transporter 4; and v) decreased fatty acid and glucose uptake and triglyceride content. DGKη was targeted for investigation based on our findings that i) DGKη was highly expressed in primary human adipocytes and time-dependently induced by t10,c12 CLA and that ii) t10,c12 CLA-induced DGKη expression was dose-dependently decreased with R59022. Small interfering RNA (siRNA) targeting DGKη decreased t10,c12 CLA-induced DGKη, IL-8, and MCP-1 gene expression, as well as activation of JNK and cJun. Taken together, these data suggest that DGKs mediate, in part, t10,c12 CLA-induced inflammatory signaling in primary human adipocytes.
AuthorsKristina Martinez, Shruthi Shyamasundar, Arion Kennedy, Chia Chi Chuang, Angel Marsh, Jennifer Kincaid, Tanya Reid, Michael McIntosh
JournalJournal of lipid research (J Lipid Res) Vol. 54 Issue 3 Pg. 662-70 (Mar 2013) ISSN: 0022-2275 [Print] United States
PMID23264678 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Chemokine CCL2
  • Enzyme Inhibitors
  • Interleukin-6
  • Interleukin-8
  • Linoleic Acids, Conjugated
  • Pyrimidinones
  • Thiazoles
  • R 59022
  • Diacylglycerol Kinase
  • Calcium
Topics
  • Adipocytes (drug effects, metabolism)
  • Calcium (metabolism)
  • Cells, Cultured
  • Chemokine CCL2 (metabolism)
  • Diacylglycerol Kinase (antagonists & inhibitors, genetics, metabolism)
  • Enzyme Inhibitors
  • Humans
  • Inflammation (chemically induced, metabolism)
  • Interleukin-6 (metabolism)
  • Interleukin-8 (metabolism)
  • Linoleic Acids, Conjugated (pharmacology)
  • Pyrimidinones (pharmacology)
  • Thiazoles (pharmacology)

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