Watt M J, Southgate R J, Holmes A G, Febbraio M A
Skeletal Muscle Research Laboratory, School of Medical Sciences, Royal Melbourne Institute of Technology, PO Box 27, Bundoora 3083, Victoria, Australia.
J Mol Endocrinol. 2004 Oct;33(2):533-44. doi: 10.1677/jme.1.01499.
Fatty acids are an important ligand for peroxisome proliferator-activated receptor (PPAR) activation and transcriptional regulation of metabolic genes. To examine whether reduced plasma free fatty acid (FFA) availability affects the mRNA content of proteins involved in fuel metabolism in vivo, the skeletal muscle mRNA content of various transcription factors, transcriptional coactivators and genes encoding for lipid regulatory proteins were examined before and after 3 h of cycle exercise with (NA) and without (CON) pre-exercise ingestion of nicotinic acid (NA). NA resulted in a marked (3- to 6-fold) increase (P<0.05) in PPARalpha, PPARdelta and PPAR coactivator 1alpha (PGC1alpha) mRNA, but was without effect on nuclear respiratory factor-1 and Forkhead transcription factor, fatty acid transcolase/CD36, carnitine palmitoyl transferase 1, hormone sensitive lipase (HSL) and pyruvate dehydrogenase kinase 4. Exercise in CON was associated with increased (P<0.05) PPARalpha, PPARdelta and PGC1alpha mRNA, which was similar in magnitude to levels observed with NA at rest. Exercise was generally without effect on the mRNA content of lipid regulatory proteins in CON and did not affect the mRNA content of the measured subset of transcription factors, transcriptional co-activators and lipid regulatory proteins during NA. To determine the possible mechanisms by which NA might affect PGC1alpha expression, we measured p38 MAP kinase (MAPK) and plasma epinephrine. Phosphorylation of p38 MAPK was increased (P<0.05) by NA treatment at rest, and this correlated (r2=0.84, P<0.01) with increased PGC1alpha. Despite this close relationship, increasing p38 MAPK in human primary myotubes was without effect on PGC1alpha mRNA content. Plasma epinephrine was elevated (P<0.05) by NA at rest (CON: 0.27+/-0.06, NA: 0.72+/-0.11 nM) and throughout exercise. Incubating human primary myotubes with epinephrine increased PGC1alpha independently of changes in p38 MAPK phosphorylation. Hence, despite the fact that NA ingestion decreased FFA availability, it promoted the induction of PPARalpha/delta and PGC1alpha gene expression to a similar degree as prolonged exercise. We suggest that the increase in PGC1alpha may be due to the elevated plasma epinephrine levels. Despite these changes in transcription factors/coactivators, the mRNA content of lipid regulatory proteins was generally unaffected by plasma FFA availability.
脂肪酸是过氧化物酶体增殖物激活受体（PPAR）激活及代谢基因转录调控的重要配体。为研究体内血浆游离脂肪酸（FFA）可用性降低是否会影响参与燃料代谢的蛋白质的mRNA含量，在进行3小时自行车运动前和运动后，分别检测了服用（NA）和未服用（CON）运动前烟酸（NA）的情况下，各种转录因子、转录共激活因子以及编码脂质调节蛋白的基因在骨骼肌中的mRNA含量。NA使PPARα、PPARδ和PPAR共激活因子1α（PGC1α）的mRNA显著增加（3至6倍）（P<0.05），但对核呼吸因子-1、叉头转录因子、脂肪酸转位酶/CD36、肉碱棕榈酰转移酶1、激素敏感性脂肪酶（HSL）和丙酮酸脱氢酶激酶4没有影响。CON组运动后PPARα、PPARδ和PGC1α的mRNA增加（P<0.05），增加幅度与NA组静息时观察到的水平相似。运动一般对CON组脂质调节蛋白的mRNA含量没有影响，且在NA组运动期间对所检测的转录因子、转录共激活因子和脂质调节蛋白子集的mRNA含量也没有影响。为确定NA可能影响PGC1α表达的潜在机制，我们检测了p38丝裂原活化蛋白激酶（MAPK）和血浆肾上腺素。静息时NA处理使p38 MAPK磷酸化增加（P<0.05），且与PGC1α增加相关（r2 = 0.84，P<0.01）。尽管存在这种密切关系，但在人原代肌管中增加p38 MAPK对PGC1α的mRNA含量没有影响。静息时NA使血浆肾上腺素升高（P<0.05）（CON组：0.27±0.06，NA组：0.72±0.11 nM），且在整个运动过程中均升高。用肾上腺素孵育人原代肌管可独立于p38 MAPK磷酸化的变化增加PGC1α。因此，尽管服用NA会降低FFA可用性，但它促进PPARα/δ和PGC1α基因表达的诱导程度与长时间运动相似。我们认为PGC1α的增加可能是由于血浆肾上腺素水平升高。尽管转录因子/共激活因子发生了这些变化，但脂质调节蛋白的mRNA含量一般不受血浆FFA可用性的影响。
