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- Title
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.
- Authors
Staiger H; Haas C; Machann J; Werner R; Weisser M; Schick F; Machicao F; Stefan N; Fritsche A; Häring HU; Staiger, Harald; Haas, Carina; Machann, Jürgen; Werner, Roman; Weisser, Melanie; Schick, Fritz; Machicao, Fausto; Stefan, Norbert; Fritsche, Andreas; Häring, Hans-Ulrich
- Abstract
<bold>Objective: </bold>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).<bold>Research Design and Methods: </bold>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).<bold>Results: </bold>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).<bold>Conclusions: </bold>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.
- Publication
Diabetes, 2009, Vol 58, Issue 3, p579
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db07-1438