Fatty acid-induced differential regulation of the genes encoding peroxisome proliferator-activated receptor-γ coactivator-1α and -1β in human skeletal muscle cells that have been differentiated in vitro
The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) 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-1α (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.
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 (C16:1ω7), oleate (C18:1ω9) or linoleate (C18:2ω6). PPARGC1A/B mRNA was quantified by RT-PCR. Mitochondrial activity was determined by formazan formation.
Untreated cells expressed 28-fold more PPARGC1B mRNA than PPARGC1A mRNA (13.33±2.86 vs 0.47±0.08 fg/μg 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).
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.
- Puigserver P, Spiegelman BM (2003) Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α): transcriptional coactivator and metabolic regulator. Endocr Rev 24:78–90
- Mootha VK, Lindgren CM, Eriksson KF et al (2003) PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273
- Patti ME, Butte AJ, Crunkhorn S et al (2003) Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A 100:8466–8471
- Ling C, Poulsen P, Carlsson E et al (2004) Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins. J Clin Invest 114:1518–1526
- Krützfeldt J, Kausch C, Volk A et al (2000) Insulin signaling and action in cultured skeletal muscle cells from lean healthy humans with high and low insulin sensitivity. Diabetes 49:992–998
- Richardson DK, Kashyap S, Bajaj M (2005) Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases expression of extracellular matrix genes in human skeletal muscle. J Biol Chem 280:10290–10297
- Watt MJ, Southgate RJ, Holmes AG, Febbraio MA (2004) Suppression of plasma free fatty acids upregulates peroxisome proliferator-activated receptor (PPAR) α and δ and PPAR coactivator 1α in human skeletal muscle, but not lipid regulatory genes. J Mol Endocrinol 33:533–544
- Zhang P, Liu C, Zhang C, Zhang Y, Shen P, Zhang J, Zhang CY (2005) Free fatty acids increase PGC-1α expression in isolated rat islets. FEBS Lett 579:1446–1452
- Lin J, Yang R, Tarr PT et al (2005) Hyperlipidemic effects of dietary saturated fats mediated through PGC-1β coactivation of SREBP. Cell 120:261–273
- Yoon JC, Puigserver P, Chen G et al (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413:131–138
- Fatty acid-induced differential regulation of the genes encoding peroxisome proliferator-activated receptor-γ coactivator-1α and -1β in human skeletal muscle cells that have been differentiated in vitro
Volume 48, Issue 10 , pp 2115-2118
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Fatty acids
- Mitochondrial activity
- Skeletal muscle cells
- Industry Sectors
- Author Affiliations
- 1. Department of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry, Eberhard-Karls-University Tübingen, Tübingen, Germany
- 2. Internal Medicine IV, Medical Clinic Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany