Muscle-Derived Angiopoietin-Like Protein 4 Is Induced by Fatty Acids via Peroxisome Proliferator-Activated Receptor (PPAR)-[delta] and Is of Metabolic Relevance in Humans

Long-chain fatty acids (LCFAs) contribute to metabolic homeostasis in part via gene regulation. This study's objective was to identify novel LCFA target genes in human skeletal muscle cells (myotubes). In vitro methods included culture and treatment of human myotubes and C2C12 cells, gene array...

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Published inDiabetes (New York, N.Y.) Vol. 58; no. 3; p. 579
Main Authors Staiger, Harald, Haas, Carina, Machann, Jürgen, Werner, Roman, Weisser, Melanie, Schick, Fritz, Machicao, Fausto, Stefan, Norbert, Fritsche, Andreas, Häring, Hans-Ulrich
Format Journal Article
LanguageEnglish
Published New York American Diabetes Association 01.03.2009
Subjects
Body fat
Coronary vessels
Diabetes
Fatty acids
Genes
Genomes
Glucose
Insulin resistance
Lipids
Magnetic resonance imaging
Metabolic syndrome
Musculoskeletal system
Peptides
Plasma
Proteins
Research design
Spectrum analysis
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Summary:Long-chain fatty acids (LCFAs) contribute to metabolic homeostasis in part via gene regulation. This study's objective was to identify novel LCFA target genes in human skeletal muscle cells (myotubes). In vitro methods included culture and treatment of human myotubes and C2C12 cells, gene array analysis, real-time RT-PCR, Western blotting, ELISA, chromatin immunoprecipitation, and RNA interference. Human subjects (two cohorts) were characterized by oral glucose tolerance test, hyperinsulinemic-euglycemic clamp, magnetic resonance imaging and spectroscopy, and standard blood analyses (glucose, insulin, C-peptide, and plasma lipids). We show here that ANGPTL4 (encoding angiopoietin-like protein 4) represents a prominent LCFA-responsive gene in human myotubes. LCFA activated peroxisome proliferator-activated receptor (PPAR)-delta, but not PPAR-alpha or -gamma, and pharmacological activation of PPAR-delta markedly induced ANGPTL4 production and secretion. In C2C12 myocytes, knockdown of PPARD, but not of PPARG, blocked LCFA-mediated ANGPTL4 induction, and LCFA treatment resulted in PPAR-delta recruitment to the ANGPTL4 gene. In addition, pharmacological PPAR-delta activation induced LIPE (encoding hormone-sensitive lipase), and this response crucially depended on ANGPTL4, as revealed by ANGPTL4 knockdown. In a human cohort of 108 thoroughly phenotyped subjects, plasma ANGPTL4 positively correlated with fasting nonesterified fatty acids (P = 0.0036) and adipose tissue lipolysis (P = 0.0012). Moreover, in 38 myotube donors, plasma ANGPTL4 levels and adipose tissue lipolysis in vivo were reflected by basal myotube ANGPTL4 expression in vitro (P = 0.02, both). ANGPTL4 is produced by human myotubes in response to LCFA via PPAR-delta, and muscle-derived ANGPTL4 seems to be of systemic relevance in humans.
ISSN:0012-1797
1939-327X