m6A甲基化与代谢性疾病的研究进展

N6-甲基腺嘌呤(N6-methyladenosine,m⁶A)是腺嘌呤(A)第6位氮原子被甲基转移酶催化形成的一种RNA甲基化修饰,是真核生物信使RNA(mRNA)上最多的化学修饰形式。近年来研究发现m⁶A对RNA在脂肪组织生成、细胞分化和免疫/炎症反应等过程中发挥重要的调控作用。代谢性疾病是由体内蛋白质、葡萄糖和脂质代谢紊乱引起的一类慢性炎症疾病。在肥胖、2型糖尿病和心血管疾病等代谢性疾病的发生发展中,m⁶A甲基化修饰通过调控糖脂代谢和免疫/炎症发挥着重要角色。文章拟对m⁶A甲基化在代谢性疾病中的作用做一综述,并从表观转录组学的角度为代谢性疾病的防治提供新的思路。     

DNA甲基转移酶基因多态性与自身免疫性疾病关系的研究进展

DNA甲基化是最常见的表观遗传修饰形式,在调控基因表达、维持基因组稳定中起着极其重要的作用。DNA甲基转移酶是催化并维持这一过程的一类酶,其单核苷酸多态性可导致DNA甲基转移酶构型、功能异常,进而影响基因组DNA甲基化水平,并通过多种机制导致自身免疫性疾病的发生、发展。本文以系统性红斑狼疮、类风湿关节炎、免疫性血小板减少症等常见自身免疫性疾病为例,重点阐述DNA甲基转移酶单核苷酸多态性与免疫性疾病易感性的关系。     

线粒体在2型糖尿病β细胞功能障碍中的作用

胰岛β细胞线粒体对β细胞胰岛素分泌功能起着十分重要的作用,线粒体呼吸链氧化磷酸化产生ATP,与胰岛素分泌相联系。其氧化磷酸化功能受线粒体DNA和核DNA的调控,且二者通过一些相关的因子联系起来,使线粒体呼吸链亚基在转录水平协同表达。其中核呼吸因子、过氧化物酶体增殖物激活受体γ共激活因子和解偶联蛋白2等起着重要作用。     

PGC-1α活性调节的信号通路

很多信号通路参与了过氧化物增殖子激活-受体因子γ辅激活因子(PGC-1α)的表达和活性调节,如Ca2+依赖通路、能量依赖调节、激素、细胞周期蛋白依赖激酶(CDKs)等代谢刺激及后翻译修饰。其中,钙将神经肌肉的活动通过钙神经素等调控通路传输到相关基因的转录变化,发挥着第二信使的作用;腺苷酸-活化蛋白激酶(AMPK)等能量物质化学诱导PGC-1α;甲状腺素能够通过直接或间接的通路控制线粒体生物发生;CDKs参与细胞循环或转录控制;脱乙酰酶(SIRT1)和AMPK等翻译后修饰增加了PGC-1α活性。PGC-1α在协调线粒体生物发生和代谢基因信号网路中发挥了中枢作用。     

线粒体在2型糖尿病β细胞功能障碍中的作用

胰岛β细胞线粒体对β细胞胰岛素分泌功能起着十分重要的作用，线粒体呼吸链氧化磷酸化产生ATP，与胰岛素分泌相联系。其氧化磷酸化功能受线粒体DNA和核DNA的调控，且二者通过一些相关的因子联系起来，使线粒体呼吸链亚基在转录水平协同表达。其中核呼吸因子、过氧化物酶体增殖物激活受体γ共激活因子和解偶联蛋白2等起着重要作用。     

METTL3在心血管疾病中的作用机制研究进展

近年来,由于RNA的甲基化修饰在基因转录后调控中发挥重要作用而引起人们高度关注。其中,RNA的N6甲基腺苷(m6A)修饰是mRNA中除5′帽子结构外含量最高的甲基化修饰。调控m6A修饰的酶分为三大类:RNA甲基转移酶、RNA去甲基化酶和RNA甲基化识别酶,它们分别对RNA的N6-腺苷酸起着催化甲基化修饰、去除甲基化修饰及识别甲基化位点的作用,进而参与下游翻译、RNA降解、控制RNA出核速度等过程。在这些酶中,METTL3作为RNA的甲基转移酶核心成分,具有调控细胞RNA整体m6A修饰的作用。心血管疾病是一类受后天环境因素影响较大的疾病,而后天环境因素通常可以通过表观遗传学的相关机制影响疾病的发生发展,故以转录后调控为核心的表观遗传学在心血管疾病研究中成为热门话题。本综述旨在对近几年与METTL3在心血管疾病中的相关研究进行简单整理总结,有望帮助后续的基础科研和临床工作者了解RNA的m6A修饰在心血管疾病发生发展机制中的研究进展。     

线粒体DNA在慢性肝病发病机制中作用的研究进展

线粒体DNA是位于线粒体基质内线粒体自有的遗传物质,参与细胞代谢和能量供给。线粒体DNA的损伤通过增加活性氧的释放加剧氧化应激,线粒体DNA释放亦可引发细胞凋亡及通过损伤相关分子模式激活免疫炎症反应。线粒体自噬则通过负反馈机制调控线粒体DNA损伤和释放,维持细胞内稳态。近年研究结果显示,慢性肝病的发生、发展与线粒体DN...     

TFAM在卵母细胞成熟和早期胚胎发育中的作用

<正>线粒体在生殖细胞的发育和功能发挥着重要的作用。线粒体含有一组母系遗传基因,在生殖细胞发育过程中应将未受活性氧损伤的线粒体遗传给后代。核基因编码的线粒体转录因子A(TFAM)是线粒体转录和翻译的重要调控因子,调控线粒体DNA的拷贝,影响卵母细胞和胚胎的发育。本文主要从TFAM对卵母细胞、胚胎影响的角度进行了综述。1 TFAM的生物学特性线粒体基因与其产物在卵母细胞的形成和发育中扮演着     

孕酮和脂联素受体3对肝脂肪酸代谢关键转录因子过氧化物酶体增殖物激活受体α翻译后修饰调控的研究

正【据《Hepatology》2018年2月报道】题:孕酮和脂联素受体3对肝脂肪酸代谢关键转录因子过氧化物酶体增殖物激活受体α翻译后修饰调控的研究(作者Zhao ZL等)肝脂质代谢稳态受多条信号通路的协同调控,在这一过程中,过氧化物酶体增殖物激活受体(PPAR)α作为一个关键的转录因子,在营养饥饿的情况下可促进肝脂肪酸氧化和酮体生成,进而提供机体所必须的能量。然而,对于PPARα的翻译后修饰调控     

肿瘤组蛋白乙酰化修饰及其临床应用研究进展

肿瘤的发生通常认为与基因突变所引起的各种调控蛋白的上调或者下调有关,然而最近观点认为,表观遗传学在肿瘤的发生及分化中起了关键性的作用.目前认为,在细胞生命活动的选择性基因沉默或基因表达过程中,包裹于染色质中的基因组DNA序列一般不发生改变;但细胞核内的染色质结构可以发生高度的动态变化,使一些特定基因组区域的转录活性呈现相应的改变.这种影响基因转录活性而不涉及DNA序列改变的基因表达调控方式称为表观遗传调控[1],其分子基础有两个方面,即针对DNA本身的修饰和对组蛋白的修饰.DNA和组蛋白的修饰通常以一种高度保守的方式,通过染色质修饰酶动态地发生改变.现在发现至少有4种不同的DNA修饰和16种组蛋白修饰方式[2,3].在肿瘤中,许多参与组蛋白修饰过程的蛋白常常失去调控.本文将目前研究最广泛的组蛋白修饰方式——组蛋白乙酰化和去乙酰化作用及其临床应用综述如下.     

Genetic factors related to mitochondrial function and risk of diabetes mellitus

Mitochondria are the intracellular organelles responsible for the generation of ATP by the process of oxidative phosphorylation (OXPHOS) and have their own DNA containing genes for 13 subunits of OXPHOS and 2 rRNAs and 22 tRNAs for their protein synthesis machinery. Since mitochondrial DNA (mtDNA) has limited coding capacity, nuclear genes make a major contribution to mitochondrial architecture, metabolic systems and biogenesis. Nowadays, there is a growing body of evidence that the mitochondrial dysfunction plays a crucial role in the pathogenesis of type 2 diabetes. In this review, we showed that mtDNA copy number in peripheral blood cells is associated with various pathophysiological characteristics of type 2 diabetes such as insulin resistance and insulin secretory defect. In addition, peripheral blood mtDNA copy number is a risk factor for the development of type 2 diabetes. Common polymorphisms in mtDNA and nuclear genes regulating mitochondrial function might be associated with type 2 diabetes. Elucidation of genetic factors regulating mitochondrial function would be of help to understand how mitochondrial dysfunction is linked to the pathogenesis of type 2 diabetes.     

The development of mitochondrial medicine.

Primary defects in mitochondrial function are implicated in over 100 diseases, and the list continues to grow. Yet the first mitochondrial defect--a myopathy--was demonstrated only 35 years ago. The field's dramatic expansion reflects growth of knowledge in three areas: (i) characterization of mitochondrial structure and function, (ii) elucidation of the steps involved in mitochondrial biosynthesis, and (iii) discovery of specific mitochondrial DNA. Many mitochondrial diseases are accompanied by mutations in this DNA. Inheritance is by maternal transmission. The metabolic defects encompass the electron transport complexes, intermediates of the tricarboxylic acid cycle, and substrate transport. The clinical manifestations are protean, most often involving skeletal muscle and the central nervous system. In addition to being a primary cause of disease, mitochondrial DNA mutations and impaired oxidation have now been found to occur as secondary phenomena in aging as well as in age-related degenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, amyotrophic lateral sclerosis and cardiomyopathies, atherosclerosis, and diabetes mellitus. Manifestations of both the primary and secondary mitochondrial diseases are thought to result from the production of oxygen free radicals. With increased understanding of the mechanisms underlying the mitochondrial dysfunctions has come the beginnings of therapeutic strategies, based mostly on the administration of antioxidants, replacement of cofactors, and provision of nutrients. At the present accelerating pace of development of what may be called mitochondrial medicine, much more is likely to be achieved within the next few years.     

Gastrointestinal and hepatic manifestations of mitochondrial disorders

Inherited defects of oxidative phosphorylation lead to heterogeneous, often multisystem, mitochondrial diseases. This review highlights those mitochondrial syndromes with prominent gastrointestinal and hepatic symptoms, categorised according to underlying disease mechanism. Mitochondrial encephalopathies with major gastrointestinal involvement include mitochondrial neurogastrointestinal encephalopathy and ethylmalonic encephalopathy, which are each associated with highly specific clinical and metabolic profiles. Mitochondrial hepatopathies are most frequently caused by defects of mitochondrial DNA maintenance and expression. Although mitochondrial disorders are notorious for extreme clinical, biochemical and genetic heterogeneity, there are some pathognomonic clinical and metabolic clues that suggest a specific diagnosis, and these are highlighted. An approach to diagnosis of these complex disorders is presented, together with a genetic classification, including mitochondrial DNA disorders and nuclear-encoded defects of mitochondrial DNA maintenance and translation, OXPHOS complex assembly and mitochondrial membrane lipids. Finally, supportive and experimental therapeutic options for these currently incurable diseases are reviewed, including liver transplantation, allogeneic haematopoietic stem cell transplantation and gene therapy.     

The role of adiponectin for immune cell function in metabolic diseases

Adiponectin, as an indispensable regulator of the immune system, is the most abundant adipokine and is mainly produced by white adipose tissue. Adiponectin mediates the positive effects on systemic metabolism by regulating associated downstream signalling pathways; however, accumulating evidence shows that adiponectin plays an important role in regulating the function of innate and adaptive immune cells in the development of obesity and its related diseases. In this review, we focus on the biological function of adiponectin in regulating innate and adaptive immunity and outline the key role of adiponectin in various metabolic diseases, which will highlight a potential direction for adiponectin-based therapeutic interventions for metabolic diseases.