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。     

PGC-1α的功能与代谢病

过氧化物酶体增殖活化受体γ辅助活化因子1α(α subunit of peroxisome proliferators activated receptor γ coactivator 1,PGC-1α)是过氧化物酶体增殖活化受体γ辅助活化因子1 (PGC 1)的成员之一. PGC-1α是与能量代谢 关系密切的1个转录辅助活化因子,在线粒体合成、调节适应性产热、骨骼肌纤维类型转换等过程中发挥重要作用.同时,还 参与到糖代谢、脂代谢中,已成为治疗糖尿病、肥胖等代谢疾病的新靶点.近年来还发现, PGC-1α对治疗癌症发生及神经 变性疾病有一定作用.本文主要从PGC-1α调节适应性产热、促进线粒体合成、在骨骼肌中调节纤维类型转换及葡萄糖代谢 等方面对其生理功能进行阐述,并对 PGC-1α与相关代谢疾病的关系进行了总结.     

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.     

PGC-1α与炎症反应的研究进展

PGC-1α是共激活转录因子成员,调控线粒体生成相关基因的转录和表达,促进线粒体生成,调节机体的能量代谢。最近的研究发现,PGC-1α也参与机体炎症反应的调控过程。本文从PGC-1α的结构与活性调节、与糖尿病、神经系统疾病的关系等方面综述PGC-1α与机体炎症调控的最新进展。     

HSF1-PGC1α介导雷公藤红素代谢调节作用

<正>雷公藤红素(celastrol)有调节机体能量平衡与代谢稳态的药理作用,并能有效抵御肥胖。新近研究揭示,雷公藤红素抵抗肥胖的药理作用,是由热休克因子1(heat shock factor-1,HSF1)和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)参与介导的。Ma等研究人员利用小鼠模型发现,雷公藤红素可激活转录因子HSF1与PGC-1α,     

PGC-1α及其在肌纤维类型转化中的作用

PGC-1α属于与能量代谢关系最密切的PGC-1转录辅助活化因子家族成员,最早在酵母双杂交体系中作为调控脂肪细胞分化的核受体PPARγ的辅激活因子被发现。PGC-1α在肌纤维类型转化中发挥重要作用,肌纤维类型及其组成是肌肉生长和肉品质形成的生物学基础,直接影响肌肉色泽、嫩度内脂肪含量。因此,研究PGC-1α在肌纤维类型转化中的调控作用,将为改善肉品质提供重要的理论依据。主要从PGC-1α的结构特点、作用特征及其在陆上动物和鱼类肌纤维类型转化中的最新进展等方面进行综述。     

Sirt1及其相关信号通路蛋白调节胰岛素敏感性的研究进展

Sirt1是哺乳动物长寿基因Sir2的同源蛋白,越来越多研究表明Sirt1在糖脂代谢和胰岛素敏感性调节中起重要作用。Sirt1具有NAD依赖的去乙酰化酶的作用,可通过一系列底物去乙酰化,参与调节胰岛素敏感性。它通过影响胰岛素敏感性密切相关的信号蛋白,包括PGC-1α、PPARγ、PTP1B、NFκB/JNK等,影响其下游信号分子的表达或活性,调节糖脂代谢,抑制脂肪组织低级炎症,进而对胰岛素敏感性起着重要的调节作用。Sirt1还通过NAD+水平与AMPK相互调节,维持细胞的能量平衡。Sirt1可能成为改善胰岛素抵抗潜在的药物作用靶点。     

人参皂苷Rb1通过上调PGC-1α缓解糖尿病心肌病

目的:研究人参皂苷Rb1对糖尿病心肌病的治疗作用并阐明其分子机制。方法:采用腹腔注射链脲佐菌素的方法,建立糖尿病心肌病动物模型。将小鼠分为3组:WT组,DM组,DM+Rb1组。超声心动图分析小鼠心功能;Western blot分析PGC-1α、cleaved caspase-3、bcl-2等蛋白表达;MitoSOX染色分析线粒体ROS含量;透射电镜分析线粒体数目。结果:与WT组相比,DM组小鼠心功能显著下降(LVEF,P<0.01),PGC-1α表达下调(P<0.01),线粒体数目减少(P<0.01);而Rb1处理后,显著改善了DM小鼠心功能(LVEF,P<0.01),恢复了PGC-1α表达(P<0.05),增加了线粒体数目(P<0.05)。同时,Rb1处理后,减少了糖尿病小鼠心肌线粒体ROS产生(P<0.01),恢复了bcl-2蛋白表达(P<0.01),降低了cleaved caspase-3蛋白表达(P<0.01),从而减少了高糖引起的细胞凋亡(P<0.05)。而siPGC-1α处理后,阻断了Rb1的上述作用。结论:人参皂苷Rb1通过上调PGC-1α改善糖尿病小鼠心功能,缓解糖尿病心肌病。其机制可能与人参皂苷Rb1降低心肌线粒体ROS产生并减少心肌细胞凋亡有关。     

PPAR-γ/PGC-1α对支气管哮喘豚鼠肺组织Nrf2/γ-GCS-h作用

目的：观察PPAR-γ、PGC-1α、Nrf2和γ-GCS-h在豚鼠支气管哮喘肺组织中表达而探索PPAR-γ/PGC-1α对Nrf2/γ-GCS-h作用。方法：40只健康雄性豚鼠随机化原则分成对照组（A组）、哮喘组（B组）、地塞米松（C组）和罗格列酮治疗组（D组）,每组10只豚鼠,卵蛋白致敏法复制哮喘模型。原位杂交检测PPAR-γ、PGC-1α、Nrf2和γ-GCS-hmRNA表达,免疫组化和Western blot检测四种蛋白表达。结果：PPAR-γ、PGC-1α、Nrf2和γ-GCS-h的mRNA哮喘组表达最低,四组表达差异有统计学意义（P均〈0.01）;免疫组化和Western blot显示PPAR-γ、PGC-1α、Nrf2和γ-GCS-h的蛋白哮喘组表达几乎都呈阴性而且以核内表达为主,四组差异均有统计学意义（P均〈0.01）。PPAR-γ表达与PGC-1α表达呈正相关,γ-GCS-h mRNA表达与PPAR-γ、PGC-1α、Nrf2核内表达均呈正相关,Nrf2表达与PPAR-γ和PGC-1α表达均呈正相关。结论：PPAR-γ、PGC-1α、Nrf2和γ-GCS-h在卵蛋白致敏急性支气管哮喘模型中表达下降;PPAR-γ/PGC-1α可通过上调Nrf2/γ-GCS-h表达提高组织的抗氧化能力,因而PPAR-γ/PGC-1α在哮喘的发病和防治可能起重要的作用。     

Effect of exercise intensity and AICAR on isoform-specific expressions of murine skeletal muscle PGC-1α mRNA: a role of β₂-adrenergic receptor activation

There are three isoforms of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) mRNA, which promotes mitochondrial biogenesis in skeletal muscles. Compared with PGC-1α-a mRNA, PGC-1α-b or PGC-1α-c mRNA is transcribed by a different exon 1 of the PGC-1α gene. In this study, effects of exercise intensity and 5-aminoimidazole-4-carboxamide-1β-d-ribofuranoside (AICAR) on isoform-specific expressions of PGC-1α were investigated. All isoforms were increased in proportion to exercise intensity of treadmill running (10-30 m/min for 30 min). Preinjection of β?-adrenergic receptor (AR) antagonist (ICI 118551) inhibited the increase in PGC-1α-b and PGC-1α-c mRNAs, but not the increase in PGC-1α-a mRNA, in response to high-intensity exercise. Although high-intensity exercise activated α2-AMP-activated protein kinase (α2-AMPK) in skeletal muscles, inactivation of α2-AMPK activity did not affect high-intensity exercise-induced mRNA expression of all PGC-1α isoforms, suggesting that activation of α2-AMPK is not mandatory for an increase in PGC-1α mRNA by high-intensity exercise. A single injection in mice of AICAR, an AMPK activator, increased mRNAs of all PGC-1α isoforms. AICAR increased blood catecholamine concentrations, and preinjection of β?-AR antagonist inhibited the increase in PGC-1α-b and PGC-1α-c mRNAs but not the increase in PGC-1α-a mRNA. Direct exposure of epitrochlearis muscle to AICAR increased PGC-1α-a but not the -b isoform. These data indicate that exercise-induced PGC-1α expression was dependent on the intensity of exercise. Exercise or AICAR injection increased PGC-1α-b and PGC-1α-c mRNAs via β?-AR activation, whereas high-intensity exercise increased PGC-1α-a expression by a multiple mechanism in which α2-AMPK is one of the signaling pathways.     

Requirement of helix 1 and the AF-2 domain of the thyroid hormone receptor for coactivation by PGC-1.

Although PGC-1 (peroxisome proliferator-activated receptor-gamma coactivator-1) has been previously shown to enhance thyroid hormone receptor (TR)/retinoid X receptor-mediated ucp-1 gene expression in a ligand-induced manner in rat fibroblast cells, the precise mechanism of PGC-1 modulation of TR function has yet to be determined. In this study, we show that PGC-1 can potentiate TR-mediated transactivation of reporter genes driven by natural thyroid hormone response elements both in a ligand-dependent and ligand-independent manner and that the extent of coactivation is a function of the thyroid hormone response element examined. Our data also show that PGC-1 stimulation of TR activity in terms of Gal4 DNA-binding domain fusion is strictly ligand-dependent. In addition, an E457A AF-2 mutation had no effect on the ligand-induced PGC-1 enhancement of TR activity, indicating that the conserved charged residue in AF-2 is not essential for this PGC-1 function. Furthermore, GST pull-down and mammalian two-hybrid assays demonstrated that the PGC-1 LXXLL motif is required for ligand-induced PGC-1/TR interaction. This agonist-dependent PGC-1/TR interaction also requires both helix 1 and the AF-2 region of the TR ligand-binding domain. Taken together, these results support the notion that PGC-1 is a bona fide TR coactivator and that PGC-1 modulates TR activity via a mechanism different from that utilized with peroxisome proliferator activator receptor-gamma.     

Free fatty acids increase PGC-1alpha expression in isolated rat islets

PGC-1alpha mRNA and protein are elevated in islets from multiple animal models of diabetes. Overexpression of PGC-1alpha impairs glucose-stimulated insulin secretion (GSIS). However, it is not well known which metabolic events lead to upregulation of PGC-1alpha in the beta-cells under pathophysiological condition. In present study, we have investigated effects of chronic hyperlipidemia and hyperglycemia on PGC-1alpha mRNA expression in isolated rat islets. Isolated rat islets are chronically incubated with 0, 0.2 and 0.4 mM oleic acid/palmitic acid (free fatty acids, FFA) or 5.5 and 25 mM glucose for 72 h. FFA dose-dependently increases PGC-1alpha mRNA expression level in isolated islets. FFA also increases PGC-1alpha expression in mouse beta-cell-derived beta TC3 cell line. In contrast, 25 mM glucose decreases expression level of PGC-1alpha. Inhibition of PGC-1alpha by siRNA improves FFA-induced impairment of GSIS in islets. These data suggest that hyperlipidemia and hyperglycemia regulate PGC-1alpha expression in islets differently, and elevated PGC-1alpha by FFA plays an important role in chronic hyperlipidemia-induced beta-cell dysfunction.     

The inhibitory effect of dexamethasone on platelet-derived growth factor-induced vascular smooth muscle cell migration through up-regulating PGC-1α expression

Dexamethasone has been shown to inhibit vascular smooth muscle cell (VSMC) migration, which is required for preventing restenosis. However, the mechanism underlying effect of dexamethasone remains unknown. We have previously demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1 alpha (PGC-1α) can inhibit VSMC migration and proliferation. Here, we investigated the role of PGC-1α in dexamethasone-reduced VSMC migration and explored the possible mechanism. We first examined PGC-1α expression in cultured rat aortic VSMCs. The results revealed that incubation of VSMCs with dexamethasone could significantly elevate PGC-1α mRNA expression. In contrast, platelet-derived growth factor (PDGF) decreased PGC-1α expression while stimulating VSMC migration. Mechanistic study showed that suppression of PGC-1α by small interfering RNA strongly abrogated the inhibitory effect of dexamethasone on VSMC migration, whereas overexpression of PGC-1α had the opposite effect. Furthermore, an analysis of MAPK signal pathways showed that dexamethasone inhibited ERK and p38 MAPK phosphorylation in VSMCs. Overexpression of PGC-1α decreased both basal and PDGF-induced p38 MAPK phosphorylation, but it had no effect on ERK phosphorylation. Finally, inhibition of PPARγ activation by a PPARγ antagonist GW9662 abolished the suppressive effects of PGC-1α on p38 MAPK phosphorylation and VSMC migration. These effects of PGC-1α were enhanced by a PPARγ agonist troglitazone. Collectively, our data indicated for the first time that one of the anti-migrated mechanisms of dexamethasone is due to the induction of PGC-1α expression. PGC-1α suppresses PDGF-induced VSMC migration through PPARγ coactivation and, consequently, p38 MAPK inhibition.