Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo , Oslo , Norway .
Arch Physiol Biochem. 2014 Feb;120(1):12-21. doi: 10.3109/13813455.2013.829105. Epub 2013 Aug 30.
The role of peroxisome proliferator-activated receptor δ (PPARδ) activation on global gene expression and mitochondrial fuel utilization were investigated in human myotubes. Only 21 genes were up-regulated and 3 genes were down-regulated after activation by the PPARδ agonist GW501516. Pathway analysis showed up-regulated mitochondrial fatty acid oxidation, TCA cycle and cholesterol biosynthesis. GW501516 increased oleic acid oxidation and mitochondrial oxidative capacity by 2-fold. Glucose uptake and oxidation were reduced, but total substrate oxidation was not affected, indicating a fuel switch from glucose to fatty acid. Cholesterol biosynthesis was increased, but lipid biosynthesis and mitochondrial content were not affected. This study confirmed that the principal effect of PPARδ activation was to increase mitochondrial fatty acid oxidative capacity. Our results further suggest that PPARδ activation reduced glucose utilization through a switch in mitochondrial substrate preference by up-regulating pyruvate dehydrogenase kinase isozyme 4 and genes involved in lipid metabolism and fatty acid oxidation.
研究了过氧化物酶体增殖物激活受体 δ (PPARδ) 激活对人肌管中整体基因表达和线粒体燃料利用的作用。PPARδ 激动剂 GW501516 激活后，仅有 21 个基因上调，3 个基因下调。通路分析显示上调的线粒体脂肪酸氧化、三羧酸循环和胆固醇生物合成。GW501516 使油酸氧化和线粒体氧化能力增加了 2 倍。葡萄糖摄取和氧化减少，但总底物氧化不受影响，表明从葡萄糖向脂肪酸的燃料转换。胆固醇生物合成增加，但脂质生物合成和线粒体含量不受影响。本研究证实，PPARδ 激活的主要作用是增加线粒体脂肪酸氧化能力。我们的结果进一步表明，PPARδ 激活通过上调丙酮酸脱氢酶激酶同工酶 4 和参与脂质代谢和脂肪酸氧化的基因，通过改变线粒体底物偏好来减少葡萄糖利用。
