Peroxisome proliferator-activated receptor-gamma coactivator-1alpha overexpression increases lipid oxidation in myocytes from extremely obese individuals.
Peroxisome proliferator-activated receptor-gamma coactivator-1alpha overexpression increases lipid oxidation in myocytes from extremely obese individuals.
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DOI：
10.2337/db09-1704
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发表时间：
2010-06
期刊：
影响因子：
7.7
通讯作者：
Houmard JA
中科院分区：
文献类型：
--
作者：
Consitt LA;Bell JA;Koves TR;Muoio DM;Hulver MW;Haynie KR;Dohm GL;Houmard JA
确定肥胖相关的人原代骨骼肌细胞（HSkMC）中脂肪酸氧化（FAO）的减少是否与线粒体含量降低有关，以及这种缺陷是否可以通过过氧化物酶体增殖物激活受体-γ共激活因子-1α (PGC-1α)的过表达来纠正。FAO研究了瘦肉（BMI 22.4±0.9 kg/m2, N = 12）和极度肥胖（45.3±1.4 kg/m2, N = 9）受试者的HSkMC。利用重组腺病毒提高HSkMC PGC-1α的表达（3.5倍和8.0倍），随后评估线粒体含量（mtDNA和细胞色素C氧化酶IV [COXIV]）、完全（标记油酸盐产生14CO2）和不完全（酸溶性代谢物[ASM]） FAO和甘油脂合成。肥胖与完全FAO减少30% （P < 0.05）相关，这伴随着不完全FAO （[14C]ASM产量/14CO2）的相对比率升高，脂肪酸向储存的分配增加，mtDNA (- 27%)， COXIV（- 35%）和线粒体转录因子（mtTFA）（- 43%）蛋白水平降低（P < 0.05）。PGC-1α过表达增加了瘦肉组和肥胖组FAO、mtDNA、COXIV、mtTFA和脂肪酸掺入甘油三酯（P < 0.05）。尽管PGC-1α过表达，但与瘦HSkMC相比，肥胖患者的FAO、甘油三酯合成、mtDNA、COXIV和mtTFA的扰动持续存在。当调整mtDNA和COXIV含量时，FAO在瘦肉组和肥胖组之间是相等的。线粒体含量降低与肥胖个体HSkMC中FAO受损有关。PGC-1α蛋白水平的增加并不能纠正肥胖相关的FAO或mtDNA含量的绝对减少，这暗示了PGC-1α丰度以外的机制。
To determine whether the obesity-related decrement in fatty acid oxidation (FAO) in primary human skeletal muscle cells (HSkMC) is linked with lower mitochondrial content and whether this deficit could be corrected via overexpression of peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α). FAO was studied in HSkMC from lean (BMI 22.4 ± 0.9 kg/m2; N = 12) and extremely obese (45.3 ± 1.4 kg/m2; N = 9) subjects. Recombinant adenovirus was used to increase HSkMC PGC-1α expression (3.5- and 8.0-fold), followed by assessment of mitochondrial content (mtDNA and cytochrome C oxidase IV [COXIV]), complete (14CO2 production from labeled oleate), and incomplete (acid soluble metabolites [ASM]) FAO, and glycerolipid synthesis. Obesity was associated with a 30% decrease (P < 0.05) in complete FAO, which was accompanied by higher relative rates of incomplete FAO ([14C]ASM production/14CO2), increased partitioning of fatty acid toward storage, and lower (P < 0.05) mtDNA (−27%), COXIV (−35%), and mitochondrial transcription factor (mtTFA) (−43%) protein levels. PGC-1α overexpression increased (P < 0.05) FAO, mtDNA, COXIV, mtTFA, and fatty acid incorporation into triacylglycerol in both lean and obese groups. Perturbations in FAO, triacylglycerol synthesis, mtDNA, COXIV, and mtTFA in obese compared with lean HSkMC persisted despite PGC-1α overexpression. When adjusted for mtDNA and COXIV content, FAO was equivalent between lean and obese groups. Reduced mitochondrial content is related to impaired FAO in HSkMC derived from obese individuals. Increasing PGC-1α protein levels did not correct the obesity-related absolute reduction in FAO or mtDNA content, implicating mechanisms other than PGC-1α abundance.