Lysophosphatidylcholine as an effector of fatty acid-induced insulin resistance |
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Authors: | Han Myoung Sook Lim Yu-Mi Quan Wenying Kim Jung Ran Chung Kun Wook Kang Mira Kim Sunshin Park Sun Young Han Joong-Soo Park Shin-Young Cheon Hyae Gyeong Dal Rhee Sang Park Tae-Sik Lee Myung-Shik |
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Affiliation: | Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea. |
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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 A2 (iPLA2) inhibitors, such as bromoenol lactone (BEL) or palmitoyl trifluoromethyl ketone (PACOCF3), prevented insulin resistance by PA. iPLA2 inhibitors or iPLA2 small interfering RNA (siRNA) attenuated JNK or IRS-1 Ser307 phosphorylation by PA. PA treatment increased LPC content, which was reversed by iPLA2 inhibitors or iPLA2 siRNA. The intracellular DAG level was increased by iPLA2 inhibitors, despite ameliorated insulin resistance. Pertussis toxin (PTX), which inhibits LPC action through the G-protein coupled receptor (GPCR)/Gαi, 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 findings implicate LPC as an important lipid intermediate that links saturated fatty acids to insulin resistance. |
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Keywords: | muscle lipids obesity diabetes phospholipase A2 |
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