原发性线粒体功能障碍与肝脏疾病

线粒体疾病是一种重要的遗传代谢性疾病,日益受到临床的重视.常累及多个器官及系统,肝脏是最常受累的器官之一.线粒体肝病可分为原发性和继发性线粒体肝病.原发性线粒体肝病占多数,常见于儿童,尤其是婴幼儿阶段,成人相对较少.本文将主要介绍儿童原发性线粒体功能缺陷所致的肝脏疾病.     

肝再生增强因子在肝脏中的作用

肝再生增强因子（ALR）除了促进肝再生，保护肝损伤之外，可能在肝脏的器官形成和发育中也发挥着重要作用。介绍了ALR在肝脏中的生物学功能和机制研究的最新进展，并归纳总结了ALR在肝脏疾病的诊断和治疗中的应用。指出ALR可能通过线粒体途径调控肝细胞的凋亡，从而参与肝脏的修复和再生。未来ALR可能作为肝衰竭患者肝再生及预后评估的候选分子，并有望成为临床治疗严重肝病和肝衰竭的有效药物。     

肝细胞线粒体自噬在非酒精性脂肪性肝病发病机制中的作用

非酒精性脂肪性肝病已成为我国第一大慢性肝病和健康体检肝生化指标异常的首要原因。线粒体自噬可降解肝脏中功能受损的线粒体和错误折叠蛋白以调节细胞死亡,同时具有维持肝脏脂质代谢稳态的作用。脂肪组织分泌的脂联素与脂联素受体2结合,可增加肝脏Kupffer细胞分泌自噬激动剂,诱导肝细胞线粒体自噬,促进脂质代谢,从而减轻肝脏炎症,为研发疗效显著和机制明确的非酒精性脂肪性肝病治疗药物提供了新思路。     

线粒体损伤在脂肪性肝病发生发展中的机制研究进展

线粒体损伤介导的肝细胞凋亡和坏死均能激活细胞水平的炎症通路,加速肝脏纤维化的进展。众多研究表明慢性肝病某些亚细胞器功能的损伤均与线粒体功能障碍有关,尤其是肝脏发生脂肪性变,这也是线粒体功能障碍基本病理改变之一。维护线粒体的功能和结构的完整性是抑制肝细胞死亡和治疗急慢性肝病最新的潜在治疗策略。本文重点就目前在脂肪性肝病研究领域有关线粒体损伤的研究作一综述。     

甲状腺功能减退对慢性肝病的影响

正常生理状态下,肝脏在甲状腺激素的代谢、降解和排泄过程中发挥着重要作用。但当肝脏发生病变时,甲状腺功能减退现象明显增加,且多数患者无明显临床症状及体征。归纳了由于各种病因引起的慢性肝病及其不同发病阶段患者甲状腺功能水平的变化,发现甲状腺激素水平的下降对预测慢性肝病发生风险、病情判断及预后评估具有重要的指导价值。研究认为部分慢性肝病患者可通过甲状腺功能的调节,进而在一定程度上起到缓解病情、改善预后的治疗效果。此外,由于甲状腺代谢异常所引发的一系列基因失调或功能紊乱有可能成为部分慢性肝病新的治疗靶点,结论有待进一步研究证实。     

硫氧还蛋白与肝纤维化相关研究进展

<正>肝纤维化是由各种原因引起慢性肝损伤的病理变化。它的特点是肝脏中细胞外基质(ECM)的过度积累,影响肝脏功能。肝纤维化的病因十分复杂,多种类型的慢性肝病均可以发展为肝纤维化。有关肝纤维化发病机制的研究主要集中在肝脏的炎症反应,氧化应激,肝细胞的生长和凋亡,以及肝星状细胞(HSC)的激活方面。硫氧还蛋白(Trx)是一种广泛存在于原核生物和真核生物体内的具有多种生物学功能的小分子量蛋     

人源化肝脏嵌合体小鼠的研究进展

目前很多重要的肝病研究结果来源于建立在小鼠模型基础上的生物学系统的体内研究.然而,小鼠与人是有差异的,所以很多研究结果不能直接推导到人体,但人的体内研究受伦理和技术等方面的制约.人源化肝脏的嵌合体(人鼠嵌合肝)小鼠是体内环境下研究人肝细胞功能、药物代谢动力学、嗜肝性病毒等领域的重要工具,并成为临床前研究由鼠到人之间的重要载体和桥梁,现将人鼠嵌合肝的研究进展综述如下.     

人源化肝脏嵌合体小鼠的研究进展

目前很多重要的肝病研究结果来源于建立在小鼠模型基础上的生物学系统的体内研究.然而,小鼠与人是有差异的,所以很多研究结果不能直接推导到人体,但人的体内研究受伦理和技术等方面的制约.人源化肝脏的嵌合体(人鼠嵌合肝)小鼠是体内环境下研究人肝细胞功能、药物代谢动力学、嗜肝性病毒等领域的重要工具,并成为临床前研究由鼠到人之间的重要载体和桥梁,现将人鼠嵌合肝的研究进展综述如下.     

沉默调节蛋白4在肝脏疾病发生发展中的作用

沉默调节蛋白(SIRT)家族是一类高度保守、依赖烟酰胺腺嘌呤二核苷(NAD+)的去乙酰化酶类,包括7个家族成员(SIRT 1~7)。定位于线粒体的SIRT-4具有去乙酰基酶、ADP-核糖转移酶、依赖NAD+蛋白脂酰胺酶和脱酰酶活性,参与线粒体蛋白翻译后修饰,调节体内多个代谢过程。由于代谢功能障碍与肝脏疾病息息相关,近些年,SIRT-4在肝脏疾病中的作用及调控机制日益受到关注。阐述了SIRT-4在病毒性肝炎、非酒精性脂肪性肝病、肝纤维化以及肝细胞癌等疾病中的作用,为这些肝脏疾病的防治提供新的视角。     

肝活检在肝脏疾病诊断中的意义

肝穿刺活组织检查(liver biopsy,LB)是一种能直接了解肝组织的病理变化,并可以做出较客观、精确诊断的检查方法.肝活检在临床上用于肝脏疑难病例的诊断早在上世纪60、70年代就已经开始,发展至今,在疾病的预后评估和治疗效果判断上也起着重要作用.随着对病毒性肝炎及抗病毒治疗、自身免疫性肝病、代谢性疾病、肝移植等检测指标研究的发展,肝活检在临床上的应用也越来越广泛,可以确诊以往不能在临床上诊断的肝病,而且对指导临床治疗,了解预后有极大的帮助.     

Targeted Mitochondrial Delivery to Hepatocytes: A Review

Defects in mitochondria are responsible for various genetic and acquired diseases. Mitochondrial transplantation, a method that involves introduction of healthy donor mitochondria into cells with dysfunctional mitochondria, could offer a novel approach to treat such diseases. Some studies have demonstrated the therapeutic benefit of mitochondrial transplantation and targeted delivery in vivo and in vitro within hepatocytes and the liver. This review discusses the issues regarding isolation and delivery of mitochondria to hepatocytes and the liver, and examines the existing literature in order to elucidate the utility and practicality of mitochondrial transplantation in the treatment of liver disease. Studies reviewed demonstrate that mitochondrial uptake could specifically target hepatocytes, address the challenge of non-specific localization of donor mitochondria, and provide evidence of changes in liver function following injection of mitochondria into mouse and rat disease models. While potential benefits and advantages of mitochondrial transplantation are evident, more research is needed to determine the practicality of mitochondrial transplantation for the treatment of genetic and acquired liver diseases.     

Can Prohibitin 1 be a Safeguard against liver disease?

Prohibitin (PHB) 1 is involved in multiple regulatory pathways in liver disease to protect hepatocytes, and its function is associated with subcellular localization. PHB1 located in the nucleus, cytoplasm and the mitochondrial inner membrane has anti-oxidative stress and anti-inflammatory effects in hepatitis and cirrhosis, which can protect liver cells from damage caused by inflammatory factors and reactive oxygen species (ROS) stimulation. The low expression of PHB1 located in the nucleus of liver cancer cells inhibits the proliferation and metastasis of liver cancer; thus, PHB1 exhibits the function of a tumor suppressor gene. Understanding the mechanisms of PHB1 in liver diseases may be useful for further research on the disease and may provide new ideas for the development of targeted therapeutic drugs in the future. Therefore, this review puts forward an overview of the role of PHB1 and its protective mechanism in liver diseases.     

Novel interactions of mitochondria and reactive oxygen/nitrogen species in alcohol mediated liver disease

Mitochondrial dysfunction is known to be a contributing factor to a number of diseases including chronic alcohol induced liver injury. While there is a detailed understanding of the metabolic pathways and proteins of the liver mitochondrion, little is known regarding how changes in the mitochondrial proteome may contribute to the development of hepatic pathologies.Emerging evidence indicates that reactive oxygen and nitrogen species disrupt mitochondrial function through post-translational modifications to the mitochondrial proteome. Indeed, various new affinity labeling reagents are available to test the hypothesis that post-translational modification of proteins by reactive species contributes to mitochondrial dysfunction and alcoholic fatty liver disease. Specialized proteomic techniques are also now available, which allow for identification of defects in the assembly of multi-protein complexes in mitochondria and the resolution of the highly hydrophobic proteins of the inner membrane. In this review knowledge gained from the study of changes to the mitochondrial proteome in alcoholic hepatotoxicity will be described and placed into a mechanistic framework to increase understanding of the role of mitochondrial dysfunction in liver disease.     

Liver disease in menopause

There are numerous physiologic and biochemical changes in menopause that can affect the function of the liver and mediate the development of liver disease. Menopause represents a state of growing estrogen deficiency, and this loss of estrogen in the setting of physiologic aging increases the likelihood of mitochondrial dysfunction, cellular senescence, declining immune responses to injury, and disarray in the balance between antioxidant formation and oxidative stress. The sum effect of these changes can contribute to increased susceptibility to development of significant liver pathology, particularly nonalcoholic fatty liver disease and hepatocellular carcinoma, as well as accelerated progression of fibrosis in liver diseases, as has been particularly demonstrated in hepatitis C virus liver disease. Recognition of the unique nature of these mediating factors should raise suspicion for liver disease in perimenopausal and menopausal women and offer an opportunity for implementation of aggressive treatment measures so as to avoid progression of liver disease to cirrhosis, liver cancer and liver failure.     

Steatotic livers are susceptible to normothermic ischemia-reperfusion injury from mitochondrial Complex-I dysfunction

AIM: To assess the effects of ischemic preconditioning (IPC, 10-min ischemia/10-min reperfusion) on steatotic liver mitochondrial function after normothermic ischemia-reperfusion injury (IRI). METHODS: Sixty male Sprague-Dawley rats were fed 8-wk with either control chow or high-fat/high-sucrose diet inducing > 60% mixed steatosis. Three groups (n = 10/group) for each dietary state were tested: (1) the IRI group underwent 60 min partial hepatic ischemia and 4 h reperfusion; (2) the IPC group underwent IPC prior to same standard IRI; and (3) sham underwent the same surgery without IRI or IPC. Hepatic mitochondrial function was analyzed by oxygraphs. Mitochondrial Complex-I, Complex-II enzyme activity, serum alanine aminotransferase (ALT), and histological injury were measured. RESULTS: Steatotic-IRI livers had a greater increase in ALT (2476 ± 166 vs 1457 ± 103 IU/L, P < 0.01) and histological injury following IRI compared to the lean liver group. Steatotic-IRI demonstrated lower Complex-I activity at baseline [78.4 ± 2.5 vs 116.4 ± 6.0 nmol/(min.mg protein), P < 0.001] and following IRI [28.0 ± 6.2 vs 104.3 ± 12.6 nmol/(min.mg protein), P < 0.001]. Steatotic-IRI also demonstrated impaired Complex-I function post-IRI compared to the lean liver IRI group. Complex-II activity was unaffected by hepatic steatosis or IRI. Lean liver mitochondrial function was unchanged following IRI. IPC normalized ALT and histological injury in steatotic livers but had no effect on overall steatotic liver mitochondrial function or individual mitochondrial complex enzyme activities. CONCLUSION: Warm IRI impairs steatotic liver Complex-I activity and function. The protective effects of IPC in steatotic livers may not be mediated through mitochondria.     

内分泌代谢与肝脏疾病之间的相互关系

越来越多的研究发现内分泌代谢疾病与肝脏疾病之间是相互影响的,内分泌代谢疾病可以引起肝脏功能的变化,反之,肝脏疾病也可以引起内分泌代谢功能的紊乱.     

Role of mitochondria in alcoholic liver disease

Alcohol abuse is the leading cause of liver related morbidity and mortality. Chronic or binge alcohol drinking causes hepatic steatosis which can develop to steatohepatitis, cirrhosis and ultimately hepatocellular carcinoma. The pathogenesis of alcoholic liver disease (ALD) is poorly characterized, however several recent studies point to a major role of mitochondria in this process. Mitochondria play a crucial role in cellular energy metabolism and in reactive species formation. Alcohol treatment causes mitochondrial DNA damage, lipid accumulation and oxidative stress. Studies in both animal models and in humans showed that alcohol administration causes changes in the mitochondrial morphology and function suggesting a role of these changes in the pathogenesis of ALD. We review recent findings on mechanisms by which alcohol negatively impacts mitochondrial biogenesis and function and we will discuss the specific intracellular pathways affected by alcohol consumption. Interestingly, recent findings indicate that a large number of mitochondrial proteins are acetylated and that mitochondrial proteins acetylation and sirtuins are modulated by alcohol. Understanding the mechanisms behind alcohol mediated impaired mitochondrial biogenesis and function may help identify potential therapeutic targets for treating ALD in humans.     

Chronic Ethanol Consumption Induces Global Hepatic Protein Hyperacetylation

Background: Although the clinical manifestations of alcoholic liver disease are well described, little is known about the molecular basis for liver injury. Recent studies have indicated that chronic alcohol consumption leads to the lysine‐hyperacetylation of several hepatic proteins, and this list is growing quickly. Methods: To identify other hyperacetylated proteins in ethanol‐fed livers, we chose a proteomics approach. Cytosolic and membrane proteins (excluding nuclei) were separated on 2D gels, transferred to PVDF and immunoblotted with antibodies specific for acetylated lysine residues. Hyperacetylated proteins were selected for trypsin digestion and mass spectrometric analysis. Results: In all, 40 proteins were identified, 11 of which are known acetylated proteins. Remarkably, the vast majority of hyperacetylated membrane proteins were mitochondrial residents. Hyperacetylated cytosolic proteins ranged in function from metabolism to cytoskeletal support. Notably, 3 key anti‐oxidant proteins were identified whose activities are impaired in ethanol‐treated cells. We confirmed that the anti‐oxidant enzyme, glutathione peroxidase 1, actin and cortactin are hyperacetylated in ethanol‐treated livers. Conclusions: Alcohol‐induced hyperacetylation of multiple proteins may contribute to the development of liver injury. The abundance of acetylated mitochondrial proteins further suggests that this modification is important in regulating liver metabolism and when perturbed, may contribute to the progression of a variety of metabolic diseases.     

Current management of liver diseases and the role of multidisciplinary approach

Liver is an organ having extremely diversified functions, ranging from metabolic and synthetic to detoxification of harmful chemicals. The multifunctionality of the liver in principle requires the multidisciplinary and pluralistic interventions for its management. Several studies have investigated liver function, dysfunction and clinic. This editorial work discusses new ideas, challenges and perspectives of current research regarding multidisciplinary and pluralistic management of liver diseases. In one hand the discussions have carried out on the involvement of extracellular vesicles, Na⁺/H⁺ exchangers, severe acute respiratory syndrome coronavirus 2 and Epstein–Barr virus infections, Drug-induced liver injury, sepsis, pregnancy, and food supplements in hepatic disorders. In the other hand this study has discussed hepatocellular carcinoma algorithms and new biochemical and imaging experiments pertaining to liver diseases. Relevant articles with an impact index value "> 0" from reference citation analysis, which is an open multidisciplinary citation analysis database based on artificial intelligence technology, have served for the study’s argumentation. This work may be a useful tool for the clinical practice and research in managing and investigating liver disorders.