Lysophosphatidylcholine as an effector of fatty acid - induced insulin resistance Myoung

  • W. Quan, J. R. Kim, +7 authors S. D. Rhee
  • Published 2011


The two major elements in the pathogenesis of type 2 diabetes are insulin resistance and b -cell failure. The biochemical mechanisms underlying these two phenomena are incompletely understood. The plasma FFA level is commonly elevated in type 2 diabetes patients ( 1 ). Furthermore, previous studies have presented evidence suggesting that FFA released from visceral fat is one of the primary culprits in the pathogenesis of insulin resistance, which is a prerequisite for the development of type 2 diabetes ( 2 ). In addition to insulin resistance, relative insulin defi ciency is necessary for the development of type 2 diabetes. In this step of b -cell failure, FFA has also been reported to play an important role as a potential effector of pancreatic b -cell dysfunction or death (lipotoxicity) ( 3, 4 ). Thus, chronically elevated FFA may contribute to both essential steps in the development of type 2 diabetes, and it represents one of the fundamental etiological mechanisms Abstract The mechanism of FFA-induced insulin resistance is not fully understood. We have searched for effector molecules(s) in FFA-induced insulin resistance. Palmitic acid (PA) but not oleic acid (OA) induced insulin resistance in L6 myotubes through C-Jun N-terminal kinase (JNK) and insulin receptor substrate 1 (IRS-1) Ser307 phosphorylation. Inhibitors of ceramide synthesis did not block insulin resistance by PA. However, inhibition of the conversion of PA to lysophosphatidylcholine (LPC) by calcium-independent phospholipase A 2 (iPLA 2 ) inhibitors, such as bromoenol lactone (BEL) or palmitoyl trifl uoromethyl ketone (PACOCF 3 ), prevented insulin resistance by PA. iPLA 2 inhibitors or iPLA 2 small interfering RNA (siRNA) attenuated JNK or IRS-1 Ser307 phosphorylation by PA. PA treatment increased LPC content, which was reversed by iPLA 2 inhibitors or iPLA 2 siRNA. The intracellular DAG level was increased by iPLA 2 inhibitors, despite ameliorated insulin resistance. Pertussis toxin (PTX), which inhibits LPC action through the G-protein coupled receptor (GPCR)/G i , reversed insulin resistance by PA. BEL administration ameliorated insulin resistance and diabetes in db/db mice. JNK and IRS-1Ser307 phosphorylation in the liver and muscle of db/db mice was attenuated by BEL. LPC content was increased in the liver and muscle of db/db mice, which was suppressed by BEL. These fi ndings implicate LPC as an important lipid intermediate that links saturated fatty acids to insulin resistance. — Han, M. S., Y-M. Lim, W. Quan, J. R. Kim, K. W. Chung, M. Kang, S. Kim, S. Y. Park, J-S. Han, S-Y. Park, H. G. Cheon, S. D. Rhee, T-S. Park, and M-S. Lee. Lysophosphatidylcholine as an effector of fatty acid-induced insulin resistance. J. Lipid Res. 2011. 52: 1234–1246.

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@inproceedings{Quan2011LysophosphatidylcholineAA, title={Lysophosphatidylcholine as an effector of fatty acid - induced insulin resistance Myoung}, author={W. Quan and J. R. Kim and K. W. Chung and M. Kang and S. Kim and S. Y. Park and J-S. Han and S-Y. Park and H. G. Cheon and S. D. Rhee}, year={2011} }