Fatty acid-induced differential regulation of the genes encoding peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -1beta in human skeletal muscle cells that have been differentiated in vitro.
OBJECTIVE
The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) enhances metabolically relevant pathways, such as gluconeogenesis, fatty acid oxidation, thermogenesis, oxidative phosphorylation and mitochondrial biogenesis. Since regulation of the expression of the gene encoding PGC-1alpha (PPARGC1A) by nutrients/metabolites has not been assessed in detail, the aim of this study was to determine whether PPARGC1A (and PPARGC1B) expression is modulated by common plasma fatty acids in human skeletal muscle cells.


METHODS
Human myotubes that had been differentiated in vitro were treated with 0.5 mmol/l myristate (C14:0), palmitate (C16:0), stearate (C18:0), palmitoleate (C16:1omega7), oleate (C18:1omega9) or linoleate (C18:2omega6). PPARGC1A/B mRNA was quantified by RT-PCR. Mitochondrial activity was determined by formazan formation.


RESULTS
Untreated cells expressed 28-fold more PPARGC1B mRNA than PPARGC1A mRNA (13.33+/-2.86 vs 0.47+/-0.08 fg/mug total RNA, n=5). PPARGC1A expression was increased two- to three-fold by all unsaturated fatty acids (UFAs) tested (p<0.05 each, n=5). In contrast, saturated fatty acids (SFAs) did not modulate PPARGC1A expression. Furthermore, the effect of linoleate was not blunted by palmitate. PPARGC1B mRNA expression was not increased by either the UFAs or the SFAs. SFAs reduced PPARGC1B expression (p<0.05 for palmitate and stearate, n=5). Notably, linoleate reversed palmitate's repressive effect on PPARGC1B. Myotube mitochondrial activity was increased by all UFAs (p<0.01 each, n=5), but was impaired by the SFA stearate (p<0.001, n=5).


CONCLUSIONS
We report here that fatty acids differentially regulated expression of the genes encoding the PGC-1 isoforms. Since these effects were accompanied by significant changes in mitochondrial activity, we suggest that the fatty acid-induced regulation of expression of these genes plays an important role in muscle oxidative metabolism.
Staiger
H
H
Department of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry, Eberhard-Karls-University Tübingen, Tübingen, Germany.
Staiger
K
K
Haas
C
C
Weisser
M
M
Machicao
F
F
Häring
H-U
HU
D002352:Carrier Proteins / Q000096:biosynthesis*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004032:Diet; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis*; D014280:Triglycerides / Q000378:metabolism
D002352:Carrier Proteins; D005227:Fatty Acids; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; C455622:PPARGC1B protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014280:Triglycerides