转录辅助活化因子PGC-1家族的生物学特性及功能

过氧化物酶体增殖物激活受体γ辅助活化因子1(PGC-1)家族共有PGC-1α,PGC-1β和PRC(PGC-1相关因子)3个成员,该家族在机体诸多代谢过程中发挥重要作用,包括调节机体适应性产热、线粒体的生成、脂质代谢、调节血糖平衡及葡萄糖转运、激活糖异生的关键酶和影响肌纤维类型的转换等.成员间功能也存在差异,PGC-1α的上述功能表现的较为明显,而PGC-1β在调节脂肪细胞分化及脂类代谢中具有独特的功能,PRC则仅发现其在调节线粒体的生物合成及细胞增殖中有作用.研究认为,通过调节PGC-1家族的生理功能,可治疗肥胖及糖尿病等疾病,尤其PGC-1β可作为改善机体胰岛素抵抗的新药物靶点.本文就PGC-1家族的特征、生理功能及相互作用研究进行简要综述.     

PGC-1α的转录调节和翻译后修饰

过氧化物酶体增殖物激活受体γ(peroxisome proliferator activated receptorγ,PPARγ)辅助激活因子-1α(PPARγcoactivator-1α,PGC-1α)是线粒体生物合成的关键调节分子.外界刺激(寒冷、饥饿、运动)一方面可以改变PGC-1α的基因和蛋白质表达水平,另一方面可以通过翻译后修饰方式调节其蛋白质活性,最终调节细胞能量代谢和线粒体生物合成过程.PGC-1α表达的异常是代谢性疾病及老年性疾病等发病的重要原因.本文就PGC-1α在转录水平和翻译后修饰水平的调节方式的最新研究进展作一综述.     

核辅激活因子PGC-1作用分子机制的研究进展

过氧化物酶体增殖物激活受体γ辅激活因子1（peroxisome proliferator-activated receptor-γ coactivator-1, PGC-1）通过结合下游转录因子广泛参与线粒体生物合成、肝糖异生等重要代谢通路调节,对于维持生物体能量动态平衡有重要生理意义。文章着重综述了基于PGC-1基因及蛋白结构基础的分子对接、组蛋白乙酰化、RNA加工等分子机制的研究现状,并初步探讨了其与代谢综合征发生的应用展望。     

PGC-1α对骨骼肌肌纤维类型及运动能力的调控作用

过氧化物酶体增殖物激活受体γ辅激活因子1α(peroxisome proliferator activated receptorγcoactivator-1α,PGC-1α)可调节能量代谢、诱导线粒体生物合成;在骨骼肌中促进肌纤维类型由IIb型或IId/x型向IIa型或I型转化;PGC-1α-b和PGC-1α-c亚型与运动耐力变化关系密切。全身性和骨骼肌特异性调节PGC-1α表达对骨骼肌肌纤维类型的转化和运动耐力的改变具有一定差异。外源性调控PGC-1α表达对提高运动耐力具有广阔发展前景。     

PGC-1α和Irisin在运动减肥中的作用机制

运动诱导骨骼肌表达过氧化物酶体增殖物激活受体γ辅助激活因子α（peroxisome proliferator-activated receptor γ coactivator-1α,PGC-1α）,PGC-1α通过多条途径参与调节骨骼肌的运动适应性。最新的研究发现PGC-1α在骨骼肌中可促进Ⅲ型纤连蛋白结构域5（fibronectin type Ⅲ domain-containing5,FNDC5）的表达,后者被转变为一种新的激素-Irisin。Irisin可使白色脂肪细胞转变为棕色脂肪细胞,因此PGC-1α和Irisin将成为肥胖症防治研究的新靶点。     

丙酮酸脱氢酶活性调控在线粒体代谢与生长平衡中的作用

丙酮酸脱氢酶多酶复合体(PDC)催化丙酮酸生成乙酰辅酶 A(acetyl-CoA)的反应是线粒体代谢与生长的调控枢纽.丙酮酸脱氢酶激酶 (PDK)/丙酮酸脱氢酶磷酸酶(PDP)对丙酮酸脱氢酶(PDH)的磷酸化 /脱磷酸化作用以及丙酮酸/乙酰辅酶A对PDH底物产物水平的调控是线粒体适应不同生理环境的代谢调节方式,而调控 PDK基因转录的上游信号恰好也是线粒体生长或生物发生的调控机制.过氧化物酶体增殖物激活受体 (PPAR)/过氧化物酶体增殖物激活受体g共激活因子-1(PGC-1) 信号通路可能是线粒体代谢与生长在基因转录水平的共同调控通路.线粒体代谢与生长经共同通路调节可维持线粒体功能与结构之间的平衡.     

核受体在骨骼肌运动适应性变化中的作用及机理

运动诱导的骨骼肌适应性变化是骨骼肌在受到长期运动刺激后出现骨骼肌质量、快慢肌纤维比例、骨骼肌线粒体生物合成、自噬和氧化代谢水平以及骨骼肌运动损伤后修复等方面的变化,导致肌肉肥大、氧化代谢能力提高,从而提高运动能力。核受体是一类配体依赖性的转录因子,主要包括雄激素受体、雌激素受体、糖皮质激素受体、过氧化物酶体增殖物活化受体、甲状腺激素受体、Rev-Erbα以及孤儿核受体Nur77、Nor1和雌激素相关受体等,它们在运动诱导的骨骼肌适应性变化中发挥了重要作用。例如,可通过影响快肌肥大促进抗阻运动对肌肉力量和爆发力的增强、慢肌纤维比例的增加以及慢肌线粒体合成、自噬和氧化代谢酶的提高等途径促进耐力运动对肌肉耐力的增强等。该文就以上核受体在骨骼肌运动性适应中的作用及机制作一综述,这对理解运动增加骨骼肌质量、提高线粒体数量和功能的机制具有重要意义,为运动防治肌肉流失、改善骨骼肌代谢提供理论依据。     

不同功率的激光刺激对小鼠C2C12成肌细胞耗氧率水平的影响及机制

目的：探讨不同功率的低强度650 nm激光刺激对C₂C₁₂成肌细胞耗氧率水平和相关蛋白的影响及其机制。方法：以体外培养的C₂C₁₂小鼠成肌细胞作为实验对象,以4×10⁵个/孔接种于牵张6孔板中,采用输出功率5 mW,波长650 nm的二极管激光进行单次刺激,激光照射剂量分别0 J/cm²（0 min）、0.4 J/cm²（12.8 min）、0.8 J/cm²（25.6 min）。实验结束后,采用耗氧率试剂盒（Luxcel Biosciences）检测细胞耗氧率;提取细胞总蛋白,采用Western blot技术检测成肌调节因子（MyoD）、过氧化物酶体增殖活化受体γ共激活因子1α（PGC-1α）、雷帕霉素靶蛋白和磷酸化蛋白（p-mTOR/mTOR）表达。结果：与对照组相比,低剂量组细胞氧化耗氧率结果、MyoD、PGC-1α蛋白表达显著增加（P<0.05）,高剂量组MyoD、PGC-1α蛋白表达显著增加（P<0.05）,p-mTOR/mTOR蛋白显著降低（P<0.05）。结论：较低剂量（0.4 J/cm²）的650 nm低强度激光增强了细胞氧化功能水平,并对细胞分化相关蛋白有一定影响。其机制可能与适宜的激光刺激影响PGC-1α蛋白的表达,进而影响线粒体氧化呼吸有关。     

低氧刺激影响PGC-1α表达研究进展

过氧化物酶体增殖物激活受体γ共激活因子-1α(peroxisome proliferator activated receptorγcoactivator-1α,PGC-1α)是参与调控机体线粒体发生、糖脂代谢、适应性产热、肌纤维类型转化等生理过程的关键转录共激活分子。而低氧刺激可通过代偿激活一系列细胞应答机制,促发机体不同组织PGC-1α表达及其介导的细胞信号调控通路重新调整,进而改变机体整个能量代谢体系。本文通过总结低氧浓度、低氧时长等多种刺激因素影响不同组织PGC-1α表达的相关研究,旨在进一步揭示不同组织PGC-1α对其低氧刺激产生代偿适应的分子机制,从而更好地解释低氧刺激下机体PGC-1α在调控全身能量代谢稳态中的重要作用。     

TRPV1 activation improves exercise endurance and energy metabolism through PGC-1α upregulation in mice

Impaired aerobic exercise capacity and skeletal muscle dysfunction are associated with cardiometabolic diseases. Acute administration of capsaicin enhances exercise endurance in rodents, but the long-term effect of dietary capsaicin is unknown. The capsaicin receptor, the transient receptor potential vanilloid 1 (TRPV1) cation channel has been detected in skeletal muscle, the role of which remains unclear. Here we report the function of TRPV1 in cultured C2C12 myocytes and the effect of TRPV1 activation by dietary capsaicin on energy metabolism and exercise endurance of skeletal muscles in mice. In vitro, capsaicin increased cytosolic free calcium and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression in C2C12 myotubes through activating TRPV1. In vivo, PGC-1α in skeletal muscle was upregulated by capsaicin-induced TRPV1 activation or genetic overexpression of TRPV1 in mice. TRPV1 activation increased the expression of genes involved in fatty acid oxidation and mitochondrial respiration, promoted mitochondrial biogenesis, increased oxidative fibers, enhanced exercise endurance and prevented high-fat diet-induced metabolic disorders. Importantly, these effects of capsaicin were absent in TRPV1-deficient mice. We conclude that TRPV1 activation by dietary capsaicin improves energy metabolism and exercise endurance by upregulating PGC-1α in skeletal muscles. The present results indicate a novel therapeutic strategy for managing metabolic diseases and improving exercise endurance.     

Sirt1 and the Mitochondria

Sirt1 is the most prominent and extensively studied member of sirtuins, the family of mammalian class III histone deacetylases heavily implicated in health span and longevity. Although primarily a nuclear protein, Sirt1’s deacetylation of Peroxisome proliferator-activated receptor Gamma Coactivator-1α (PGC-1α) has been extensively implicated in metabolic control and mitochondrial biogenesis, which was proposed to partially underlie Sirt1’s role in caloric restriction and impacts on longevity. The notion of Sirt1’s regulation of PGC-1α activity and its role in mitochondrial biogenesis has, however, been controversial. Interestingly, Sirt1 also appears to be important for the turnover of defective mitochondria by mitophagy. I discuss here evidences for Sirt1’s regulation of mitochondrial biogenesis and turnover, in relation to PGC-1α deacetylation and various aspects of cellular physiology and disease.     

Cardiac hypertrophy drives PGC-1α suppression associated with enhanced O-glycosylation

The peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolism and is essential for normal cardiac function. Its activity is suppressed during pressure overload induced cardiac hypertrophy and such suppression at least partially contributes to the associated morbidity. The O-linked β-N-acetylglucosamine post-translational modification (O-GlcNAc) of proteins is a glucose-derived metabolic signal. The relationship between O-GlcNAc, and PGC-1α activity in cardiac hypertrophy is unknown. We hypothesized that hypertrophy-induced suppression of PGC-1α was at least partially regulated by O-GlcNAc signaling. Treatment of neonatal rat cardiac myocytes with phenylephrine (an inducer of cardiomyocyte hypertrophy) significantly enhanced global O-GlcNAc signaling. Quantitative real-time PCR analysis revealed a downregulation of PGC-1α with concomitant suppression of fatty acid oxidation/mitochondrial genes. Transverse aortic constriction in mice decreased the basal expression of PGC-1α and its downstream genes. Reduction of O-GlcNAc signaling alleviated suppression of PGC-1α and most of its downstream genes. Interestingly, augmentation of O-GlcNAc signaling with glucosamine or PUGNAC (a O-GlcNAcase inhibitor) reduced glucose starvation-induced PGC-1α upregulation even in the absence of hypertrophy. Finally, we found that PGC-1α itself is O-GlcNAcylated. Together, these results reveal the recruitment of O-GlcNAc signaling as a potentially novel regulator of PGC-1α activity during cardiac hypertrophy. Furthermore, O-GlcNAc signaling may mediate constitutive suppression of PGC-1α activity in the heart. Such findings illuminate new possibilities regarding the inter-regulation of O-GlcNAc signaling and also may have some implications for metabolic dysregulation during cardiac diseases.