Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Inchon 406-840, Korea.
J Lipid Res. 2011 Jun;52(6):1234-1246. doi: 10.1194/jlr.M014787. Epub 2011 Mar 28.
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)/Gα(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 findings implicate LPC as an important lipid intermediate that links saturated fatty acids to insulin resistance.
游离脂肪酸（FFA）诱导的胰岛素抵抗的机制尚不完全清楚。我们一直在寻找 FFA 诱导的胰岛素抵抗中的效应分子（s）。棕榈酸（PA）而不是油酸（OA）通过 c-Jun N-末端激酶（JNK）和胰岛素受体底物 1（IRS-1）丝氨酸 307 磷酸化诱导 L6 肌管发生胰岛素抵抗。神经酰胺合成抑制剂不能阻断 PA 诱导的胰岛素抵抗。然而，钙非依赖性磷脂酶 A₂（iPLA₂）抑制剂（如溴烯诺内酯（BEL）或棕榈酰三氟甲基酮（PACOCF₃））抑制 PA 向溶血磷脂酰胆碱（LPC）的转化，可防止 PA 诱导的胰岛素抵抗。iPLA₂抑制剂或 iPLA₂小干扰 RNA（siRNA）减弱了 PA 诱导的 JNK 或 IRS-1 丝氨酸 307 磷酸化。PA 处理增加了 LPC 含量，而 iPLA₂抑制剂或 iPLA₂ siRNA 则逆转了这一过程。尽管胰岛素抵抗得到改善，但 iPLA₂抑制剂增加了细胞内 DAG 水平。百日咳毒素（PTX）通过 G 蛋白偶联受体（GPCR）/Gα（i）抑制 LPC 作用，可逆转 PA 诱导的胰岛素抵抗。BEL 给药可改善 db/db 小鼠的胰岛素抵抗和糖尿病。 BEL 可减轻 db/db 小鼠肝脏和肌肉中 JNK 和 IRS-1 丝氨酸 307 的磷酸化。db/db 小鼠肝脏和肌肉中的 LPC 含量增加，BEL 可抑制其含量。这些发现表明 LPC 是一种重要的脂质中间产物，可将饱和脂肪酸与胰岛素抵抗联系起来。
