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Lysophosphatidylcholines activate PPARδ and protect human skeletal muscle cells from lipotoxicity.
Biochim Biophys Acta. 2016 12; 1861(12 Pt A):1980-1992.BB

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.

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Authors+Show Affiliations

Klingler C
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.
Zhao X
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China.
Adhikary T
Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Hans-Meerwein-Strasse 3, Philipps University, 35043 Marburg, Germany.
Li J
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China.
Xu G
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China.
Häring HU
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.
Schleicher E
Division of Pathobiochemistry and Clinical Chemistry, University Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany.
Lehmann R
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.
Weigert C
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.

MeSH

Angiopoietin-like 4 ProteinAngiopoietinsBenzamidesCarnitine O-PalmitoyltransferaseDNA-Binding ProteinsFatty AcidsGene ExpressionHumansInflammationLysophosphatidylcholinesMuscle CellsMuscle Fibers, SkeletalMuscle, SkeletalPPAR deltaPerilipin-2Protective AgentsProtein KinasesSulfonesThiophenesTranscription, GeneticTranscriptomeUp-Regulation

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27697477

Citation

Klingler, Christian, et al. "Lysophosphatidylcholines Activate PPARδ and Protect Human Skeletal Muscle Cells From Lipotoxicity." Biochimica Et Biophysica Acta, vol. 1861, no. 12 Pt A, 2016, pp. 1980-1992.
Klingler C, Zhao X, Adhikary T, et al. Lysophosphatidylcholines activate PPARδ and protect human skeletal muscle cells from lipotoxicity. Biochim Biophys Acta. 2016;1861(12 Pt A):1980-1992.
Klingler, C., Zhao, X., Adhikary, T., Li, J., Xu, G., Häring, H. U., Schleicher, E., Lehmann, R., & Weigert, C. (2016). Lysophosphatidylcholines activate PPARδ and protect human skeletal muscle cells from lipotoxicity. Biochimica Et Biophysica Acta, 1861(12 Pt A), 1980-1992. https://doi.org/10.1016/j.bbalip.2016.09.020
Klingler C, et al. Lysophosphatidylcholines Activate PPARδ and Protect Human Skeletal Muscle Cells From Lipotoxicity. Biochim Biophys Acta. 2016;1861(12 Pt A):1980-1992. PubMed PMID: 27697477.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lysophosphatidylcholines activate PPARδ and protect human skeletal muscle cells from lipotoxicity. AU - Klingler,Christian, AU - Zhao,Xinjie, AU - Adhikary,Till, AU - Li,Jia, AU - Xu,Guowang, AU - Häring,Hans-Ulrich, AU - Schleicher,Erwin, AU - Lehmann,Rainer, AU - Weigert,Cora, Y1 - 2016/09/30/ PY - 2016/07/04/received PY - 2016/09/19/revised PY - 2016/09/29/accepted PY - 2016/10/22/pubmed PY - 2017/10/20/medline PY - 2016/10/5/entrez KW - AMPK KW - Diabetes KW - Human myotubes KW - Lysophospholipids KW - Nuclear receptors/lipid ligands KW - Skeletal muscle KW - Transcription SP - 1980 EP - 1992 JF - Biochimica et biophysica acta JO - Biochim Biophys Acta VL - 1861 IS - 12 Pt A N2 - 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. SN - 0006-3002 UR - https://www.unboundmedicine.com/medline/citation/27697477/Lysophosphatidylcholines_activate_PPARδ_and_protect_human_skeletal_muscle_cells_from_lipotoxicity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1388-1981(16)30266-9 DB - PRIME DP - Unbound Medicine ER -
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