title: Lysophosphatidylcholine as an effector of fatty acid-induced insulin resistance.
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)/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.
authors: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors: Myoung Sook
authors: MS
authors: Han
authors: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors: Yu-Mi
authors: YM
authors: Lim
authors: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors: Wenying
authors: W
authors: Quan
authors: Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Inchon 406-840, Korea.
authors: Jung Ran
authors: JR
authors: Kim
authors: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors: Kun Wook
authors: KW
authors: Chung
authors: Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors: Mira
authors: M
authors: Kang
authors: Carcinogenesis Branch, Korean National Cancer Center, Goyang 410-769, Korea.
authors: Sunshin
authors: S
authors: Kim
authors: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors: Sun Young
authors: SY
authors: Park
authors: Institute of Biomedical Science, College of Medicine, Hanyang University, Seoul 133-791, Korea; Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 133-791, Korea.
authors: Joong-Soo
authors: JS
authors: Han
authors: Institute of Biomedical Science, College of Medicine, Hanyang University, Seoul 133-791, Korea; Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 133-791, Korea.
authors: Shin-Young
authors: SY
authors: Park
authors: Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Inchon 406-840, Korea.
authors: Hyae Gyeong
authors: HG
authors: Cheon
authors: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Daejon 305-343, Korea.
authors: Sang
authors: S
authors: Dal Rhee
authors: Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Inchon 406-840, Korea. Electronic address: tspark@gachon.ac.kr.
authors: Tae-Sik
authors: TS
authors: Park
authors: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea. Electronic address: mslee0923@skku.edu.
authors: Myung-Shik
authors: MS
authors: Lee
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008244:Lysophosphatidylcholines / Q000032:analysis / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal; D009281:Naphthalenes / Q000494:pharmacology; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D054512:Phospholipases A2, Calcium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011753:Pyrones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001798:Blood Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008244:Lysophosphatidylcholines; D009281:Naphthalenes; C400481:PLIalpha; D011753:Pyrones; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D019308:Palmitic Acid; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D037342:Pertussis Toxin; D048031:JNK Mitogen-Activated Protein Kinases; D054512:Phospholipases A2, Calcium-Independent; D005947:Glucose