title: Lysophosphatidylcholines activate PPARδ and protect human skeletal muscle cells from lipotoxicity.
abstract: Metabolomics studies of human plasma demonstrate a correlation of lower plasma lysophosphatidylcholines (LPC) concentrations with insulin resistance, obesity, and inflammation. This relationship is not unraveled on a molecular level. Here we investigated the effects of the abundant LPC(16:0) and LPC(18:1) on human skeletal muscle cells differentiated to myotubes. Transcriptome analysis of human myotubes treated with 10μM LPC for 24h revealed enrichment of up-regulated peroxisome proliferator-activated receptor (PPAR) target transcripts, including ANGPTL4, PDK4, PLIN2, and CPT1A. The increase in both PDK4 and ANGPTL4 RNA expression was abolished in the presence of either PPARδ antagonist GSK0660 or GSK3787. The induction of PDK4 by LPCs was blocked with siRNA against PPARD. The activation of PPARδ transcriptional activity by LPC was shown as PPARδ-dependent luciferase reporter gene expression and enhanced DNA binding of the PPARδ/RXR dimer. On a functional level, further results show that the LPC-mediated activation of PPARδ can reduce fatty acid-induced inflammation and ER stress in human skeletal muscle cells. The protective effect of LPC was prevented in the presence of the PPARδ antagonist GSK0660. Taking together, LPCs can activate PPARδ, which is consistent with the association of high plasma LPC levels and PPARδ-dependent anti-diabetic and anti-inflammatory effects.
authors.affiliation: Division of Pathobiochemistry and Clinical Chemistry, University Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764 München-Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Klingler
authors.affiliation: CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China.
authors.forename: Xinjie
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Hans-Meerwein-Strasse 3, Philipps University, 35043 Marburg, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Adhikary
authors.affiliation: CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China.
authors.forename: Guowang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Division of Pathobiochemistry and Clinical Chemistry, University Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764 München-Neuherberg, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: Division of Pathobiochemistry and Clinical Chemistry, University Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany.
authors.forename: Erwin
authors.initials: E
authors.lastname: Schleicher
authors.affiliation: Division of Pathobiochemistry and Clinical Chemistry, University Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764 München-Neuherberg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Lehmann
authors.affiliation: Division of Pathobiochemistry and Clinical Chemistry, University Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764 München-Neuherberg, Germany. Electronic address: cora.weigert@med.uni-tuebingen.de.
authors.forename: Cora
authors.initials: C
authors.lastname: Weigert
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D032342:Muscle Cells; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism*; D000070780:Perilipin-2 / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D013450:Sulfones / Q000378:metabolism / Q000494:pharmacology; D013876:Thiophenes / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C547957:4-chloro-N-(2-((5-trifluoromethyl-2-pyridyl)sulfonyl)ethyl)benzamide; C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D001549:Benzamides; D004268:DNA-Binding Proteins; D005227:Fatty Acids; C529769:GSK0660; D008244:Lysophosphatidylcholines; D047494:PPAR delta; D000070780:Perilipin-2; D020011:Protective Agents; D013450:Sulfones; D013876:Thiophenes; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4
keywords: AMPK; Diabetes; Human myotubes; Lysophospholipids; Nuclear receptors/lipid ligands; Skeletal muscle; Transcription