酒精性脂肪肝脂质代谢研究进展

酒精性脂肪肝(AFL)是长期大量饮用酒精引发的肝脏损害性病变,可逆转也可进一步发展为肝纤维化和肝硬化。众多的脂肪细胞因子如瘦素(Leptin)、抵抗素(Resistin)和肿瘤坏死因子-α(TNF-α)在脂肪肝的发病中起到一定的促进作用,脂联素(Adiponectin)能改善脂质代谢,延缓脂肪肝的发生;脂联素通过腺苷酸活化蛋白激酶(AMPK)调节糖脂代谢、改善胰岛素敏感性。脂联素/AMPK信号通路是酒精在肝脏的作用靶点、也是调节PPARγ作用的重要信号通路;脂肪分化相关蛋白(ADRP)调节脂质代谢、促进酒精性脂肪肝的形成;过氧化物酶增殖体激活受体γ(PPARγ)参与机体脂质稳态的调节,脂肪肝时PPARγ表达增高,肝纤维化时PPARγ表达减少。对酒精性脂肪肝脂质代谢的深入研究,有助于阐明酒精性脂肪肝发病机制并为临床防治ALD及脂质代谢相关疾病提供新策略。     

肝脏非实质细胞在非酒精性脂肪性肝炎中的作用研究进展

非酒精性脂肪性肝病是全球最流行的肝脏疾病,其疾病谱包含非酒精性脂肪肝、非酒精性脂肪性肝炎、与非酒精性脂肪性肝炎相关的纤维化、肝硬化和肝细胞癌。非酒精性脂肪性肝炎是非酒精性脂肪性肝病进展性的肝脏病理表征,临床上需要药物治疗或其他治疗方式干预,但目前全球尚无针对非酒精性脂肪性肝炎的药物获批上市。非酒精性脂肪性肝炎发病机制复杂,涉及多种细胞内、细胞间的交互作用以及复杂的分子信号通路。非酒精性脂肪性肝炎治疗是一个尚未被满足的巨大临床需求。综述了肝脏中几种主要的非实质细胞在非酒精性脂肪性肝炎发病中的重要作用,同时探讨了非酒精性脂肪性肝炎药物开发靶点与不同细胞之间的相关性。     

瘦素与非酒精性脂肪肝的研究进展

瘦素(Leptin)是一种肥胖基因的多肽激素编码,通过结合到其特异性受体,发挥其在中枢神经系统和外周组织的生物效应。近年来研究发现瘦素参与了非酒精性脂肪肝的发生发展过程。因此,阐释瘦素与非酒精性脂肪肝的关系和可能机制,对疾病的防治和预后具有重要意义。本文综述了瘦素及其受体的分布、瘦素在肝组织中的生理作用以及瘦素与非酒精性脂肪肝发生发展关系的研究进展。     

肝细胞程序性坏死在肝损伤中的研究进展

各种致病因子损伤肝脏时会导致肝细胞死亡。持续的肝细胞死亡将诱发并加重慢性炎症与纤维化,最终引起肝硬化,甚至肝癌。因此,控制肝细胞死亡是改善肝损伤的有效策略。程序性坏死(necroptosis)是指一种受信号分子调控,具有典型坏死样形态的新的细胞死亡形式。现已证实,细胞程序性坏死在药源性肝损伤、免疫性肝损伤、酒精性脂肪肝、非酒精性脂肪肝、肝纤维化等多种肝损伤中扮演着重要角色。该文就近年来肝细胞程序性坏死在肝损伤中的研究进展作一综述,旨在为肝脏疾病的病理机制与相关治疗药物的研究提供新的视角和靶标。     

白介素1家族在脂肪肝疾病中的作用及机制研究进展

白介素1(interleukin-1,IL-1)炎症因子家族在脂肪肝疾病进程中发挥关键作用。IL-1炎性因子家族参与脂肪肝疾病发生发展的各个阶段,如肝炎、肝纤维化、肝硬化、肝癌,抑制IL-1信号转导途径可能是目前治疗脂肪肝疾病的有效策略。IL-1炎症因子家族多环节多途径地整体调节脂肪肝疾病的发生发展,有望成为有效治疗脂肪肝的药物靶点,指导脂肪肝治疗药物的筛选。该文对近年来关于IL-1炎症因子家族在酒精性和非酒精性脂肪肝疾病中的作用及机制研究进行全面综合、整理和归纳。     

大鼠酒精性肝病模型的建立及与瘦素关系的研究

瘦素（1eptin）是ob基因的产物，参与肝脏对脂质代谢的调节作用，与酒精性肝病有着密切的关系。研究已经发现血清瘦素水平是脂肪肝的独立危险因素，并且也可能是是脂肪性肝纤维化发生发展中的重要因子；此外肝硬化也与瘦素有着一定的关系幢。本研究采用生理途径建立大鼠酒精性肝病模型，并初步探讨瘦素与酒精性肝病的关系。     

脂肪细胞因子与非酒精性脂肪肝病

非酒精性脂肪肝病是发病率仅次于病毒性肝炎的常见肝病,是隐原性肝硬化的主要危险因素之一。多种脂肪细胞因子参与了脂肪肝的病理过程。本文就脂联素、瘦素、抵抗素、内脏脂肪素、Apelin、肠凝集素、网膜素等7种脂肪细胞因子与非酒精性脂肪肝的关系研究进展作一综述。     

炎症小体介导的细胞焦亡在非酒精性脂肪肝病中的作用及机制

非酒精性脂肪肝病包含单纯性脂肪肝、非酒精性脂肪肝炎和肝硬化等一系列病变,是造成肝硬化、肝细胞癌症的主要因素和肝脏器官移植的重要诱因。非酒精性脂肪肝的发病机制尚不明确,除了加强运动、改善饮食习惯外,目前尚无公认有效的药物治疗方式。细胞焦亡是一种新发现的程序性细胞死亡方式,依赖于天冬氨酸特异性半胱氨酸蛋白酶1（caspase-1）或caspase-11等介导的炎性小体的激活。细胞焦亡过程中常伴有炎症反应的发生,而炎症小体则是细胞产生焦亡和炎症反应所必需的多聚体蛋白复合物,其主要功能是活化caspase-1,从而间接调控炎症因子白介素1（IL-1）和IL-18的表达和分泌。最近的研究表明,细胞焦亡和炎症小体在非酒精性脂肪肝病的发生发展中起重要作用。针对该领域的最新研究进行综述,以期为非酒精性脂肪肝的防治提供新的科学认识和信息。     

天然免疫与非酒精性脂肪肝病

肝脏中大量的巨噬细胞、自然杀伤细胞(natural killer,NK)、自然杀伤T细胞(natural killer T cell,NKT)等构成了天然免疫系统.这一系统细胞功能紊乱,发生Th-1极化,使促炎症因子产生增多,促进了非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)的形成;肝脏持续的暴露于这些炎症因子,可以促进多种促纤维化因子产生,但Th-2细胞因子分泌的不足, 使NASH进一步发展为肝硬化的现象却相对比较少见.本文就肝脏天然免疫系统在非酒精性脂肪肝病(nonalcoholic fatty liver disease, NAFLD)中的调节机制作一综述.     

高脂诱导非酒精性脂肪肝动物模型及其病理机制研究进展

非酒精性脂肪肝是非酒精引起的肝脏脂肪变性及炎症的生化和组织学改变的疾病,是引发肝硬化的重要病因。为了阐明疾病的发病机制、筛选有效的防治措施,采用动物模型开展实验研究已成为科研攻关有效手段。高脂饮食所诱导的非酒精性脂肪肝动物模型最为常见,本文就高脂诱导的非酒精性脂肪肝动物模型和其可能机制进行综述。     

Impaired function of hepatic natural killer cells from murine chronic HBsAg carriers

In the present study, we demonstrated hepatic NK cells in murine chronic HBsAg carriers for the first time. It was found that the number of hepatic NK cells was decreased; natural activation of hepatic NK cells was declined; and cytotoxicity of hepatic NK cells was attenuated, which might relate to the down-regulated expression of TRAIL on hepatic NK cells. Additionally, the response of hepatic NK cells to the specific stimulation of Poly (I:C) in murine chronic HBsAg carriers was changed. The increase in anti-tumor cytotoxic activity of intrahepatic activated NK cells was markedly impaired in the transgenic mice. The transgenic mice used here had high incidence of hepatocellular carcinoma, which might result from the relative weak reactivity and impaired anti-tumor activity of NK cells in the liver. Furthermore, remarkable liver injury was observed after stimulation of Poly (I:C), demonstrating the hypersensitivity to Poly (I:C) of murine chronic HBsAg carriers which might be related to the accumulated NK cells in the liver. Why the murine chronic HBsAg carriers are characterized with impaired hepatic NK cells and the implication of the impaired hepatic NK cells in pathogenesis of HBV-related diseases, such as hepatocellular carcinoma and recrudescent hepatitis, is worth of further investigating. These results of the functions of hepatic NK cells in murine chronic HBsAg carriers would contribute to interpreting the immune responses of NK cells in the liver and the immunological mechanisms of liver diseases in human chronic HBsAg carriers.     

反义核酸药物脂质体肝靶向性的研究

目的研究反义核酸药物脂质体给药系统的肝主动靶向性。方法采用薄膜分散法制备脂质体,以花青染料荧光标记脂质体,以荧光分光光度法定量分析;利用肝组织的体内冷冻切片和小鼠体内组织分布研究肝靶向性;检测大鼠肝非实质细胞与肝实质细胞的荧光强度(INPC和IPC)。结果主动靶向脂质体在肝脏中的荧光强度明显强于非主动靶向脂质体,相对摄取率(re)为5.64;非主动靶向脂质体的荧光值比(IPC/INPC)为1.16±0.89,主动靶向脂质体的IPC/INPC为8.24±1.37。结论主动靶向脂质体具有良好的肝实质细胞靶向性和肝靶向性。     

Kupffer细胞在肝纤维化形成与转归中的作用

肝纤维化是由于反复肝损伤引起持续性炎症反应、瘢痕组织形成，导致正常组织结构破坏甚至器官衰竭的一类疾病。临床研究和动物实验均证实，肝脏内慢性长期炎症是导致过量瘢痕形成的主要诱因。在肝损伤期，Kupffer细胞快速激活并释放大量可溶性调节因子(包括过氧化物、细胞因子和蛋白酶等)，刺激肝星状细胞增殖、迁移和活化。另一方面，有研究显示，Kupffer细胞还参与肝纤维化转归，其功能可能与调节星状细胞的生物学活性及促进细胞外基质的降解有关。因此，深入研究Kupffer细胞的生物学特性以及在细胞因子环境下与星状细胞间的相互作用，对于理解肝纤维形成的病理学过程和肝纤维化转归的生理学机制具有重要的指导意义。     

Coupling of 5-fluoro 2'-deoxyuridine to lactosaminated poly-l-lysine: an approach to a regional, non-invasive chemotherapy of liver micrometastases

Nucleoside analogs conjugated with galactosyl-terminating peptides selectively enter liver cells and after intracellular release from the carrier partly exit into bloodstream, resulting in higher concentrations in liver blood than in systemic circulation. The aim of the present experiments was to ascertain whether, in mice injected with non-toxic doses of a 5-fluoro 2'-deoxyuridine (FUdR) conjugate with lactosaminated poly-L-lysine (L-poly(LYS)), the drug was released by hepatic cells in high enough amounts to be pharmacologically active on neoplastic cells infiltrating the liver. We observed that L-poly(LYS)-FUdR inhibited the growth of hepatic metastases induced by intrasplenic administration of murine colon carcinoma C-26 cells. L-poly(LYS)-FUdR was not toxic for C-26 cells in vitro, was selectively taken up by mouse liver, and was stable in mouse blood, indicating that the effect on the metastases was due to FUdR (and/or its active metabolites) released in liver blood after the conjugate was taken up by the hepatic cells. These results suggest that L-poly(LYS)-FUdR might be useful in adjuvant chemotherapy of tumors giving liver metastases. The drug released from hepatic cells into liver blood following conjugate administration via the peripheral venous route might accomplish a locoregional, non-invasive treatment of micrometastases nourished by liver sinusoids.     

CDK4在病毒性肝炎肝组织中表达的意义

目的探讨ＣＤＫ４在病毒性肝炎肝组织中表达的意义。方法对６２例病毒性肝炎、肝炎肝硬变及原发性肝癌肝组织进行ＣＤＫ４免疫组化检测。结果ＣＤＫ４阳性物质在病毒性急慢性肝炎间质（包括间质细胞）,肝细胞核、肝细胞浆、血窦等部位均有表达;在肝炎肝硬变和原发性肝癌,除间质有分布外,主要表达在肝细胞或癌细胞的胞浆中,细胞核和血窦无表达。结论　病毒性急慢性肝炎肝细胞核中ＣＤＫ４表达增强可能有利于肝组织损伤的修复。     

肝星状细胞激活与增殖相关信号转导通路在肝纤维化中的作用及机制

肝星状细胞激活和增殖在肝纤维化的发生过程中占有重要的地位。控制肝星状细胞的激活和增殖并逆肝纤维化的进程是抗肝纤维化研究的重点之一。本综述以肝星状细胞激活与增殖相关信号转导通路为中心,探讨其在肝纤维化发病作用方面的作用机制。通过干预细胞外信号传导通路,为研究肝纤维化的发病机制和药物治疗提供新的途径。     

木犀草素抑制PKM2继而促进自噬诱导肝癌细胞凋亡

目的：探究木犀草素对人肝癌HepG2细胞中PKM2表达的影响，继而挖掘木犀草素诱导肝癌细胞凋亡的机制。方法：通过数据库比较肝癌的癌旁组织和肿瘤组织中的PKM2表达差异，收集肝癌患者标本，检测癌和癌旁组织中PKM2 mRNA和蛋白的表达差异。木犀草素刺激肝癌细胞HepG2，用CCK8、流式凋亡及Western blot方法检测木犀草素对肝癌生存率和凋亡的影响，以及木犀草素作用于肝癌细胞后PKM2的变化。在肝癌细胞系中敲减或过表达PKM2，用木犀草素刺激肝癌细胞，探究PKM2对木犀草素诱导肝癌细胞增殖和凋亡的影响，同时检测自噬相关分子，探究PKM2及木犀草素对自噬的影响。结果：与癌旁组织相比，肿瘤组织中PKM2表达量升高；木犀草素以浓度依赖性和时间依赖性抑制HepG2细胞增殖，诱导细胞凋亡，并且随着木犀草素浓度的增高PKM2的表达逐渐降低；敲减PKM2可以显著抑制肝癌细胞增殖，促进肝癌细胞凋亡，而过表达PKM2可以削弱木犀草素对肝癌细胞的凋亡作用。木犀草素可以促进肝癌细胞自噬，敲减PKM2后可以抑制木犀草素诱导的自噬。结论：木犀草素可以通过抑制PKM2表达，诱导肝癌细胞发生自噬，促进细胞凋亡。     

Role of osteopontin in regulating hepatic inflammatory responses and toxic liver injury

Osteopontin (OPN) produced by cells of the immune system, epithelial tissue, smooth muscle cells, osteoblasts and tumor cells has been implicated in various pathophysiological functions such as cell binding, spreading and migration, and tumor metastasis. OPN is known to bind to integrins expressed on macrophages through the arginine-glycine-aspartic acid (RGD) motif and promote migration of cells resulting in granuloma. In the liver, it has been reported that hepatic Kupffer cells secrete OPN facilitating macrophage infiltration in necrotic areas following carbon tetrachloride liver toxicity. Recent work has underlined the importance of OPN as a pivotal cytokine/chemokine in the generated hepatic neutrophil response during early phase alcoholic liver injury. Increased hepatobiliary OPN expression correlated well with higher neutrophil infiltration in a rat model of alcoholic steatohepatitis. In the same model of alcoholic steatohepatitis, higher hepatic expression of OPN in females was attributed to the higher neutrophil infiltration and consequent higher female sensitivity to liver damage. OPN as a potential biomarker for inflammatory liver disease has also been recently assessed. This review will focus on studies demonstrating the role of OPN in mediating hepatic inflammation (neutrophils, monocytes/macrophages and lymphocytes) and the ensuing liver toxicity.     

熊果酸和齐墩果酸抗肝脂肪变和纤维化作用研究进展

熊果酸和齐墩果酸的抗氧化作用能对抗各种原因引起的氧化应激所致的肝组织脂质过氧化反应、炎性损伤、脂肪变和纤维化。熊果酸和齐墩果酸通过阻断两面神激酶2-信号传导及转录激活因子3（JAK2-STAT₃）信号转导,抑制还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）活化,阻止静息态肝星状细胞活化、增殖,促进活化态肝星状细胞凋亡,从而减少胶原生成、增加细胞外基质降解,产生防治肝纤维化的作用。熊果酸和齐墩果酸诱导肝脏去毒酶和外排转运体表达,降低胆汁淤积动物血清胆汁酸、胆红素水平和肝脏胆汁酸水平,减轻胆汁淤积性肝损伤和纤维化;还可通过降血脂作用抑制肝外脂质在肝脏沉积、抑制肝脏脂质生物合成和促进脂质代谢,阻滞肝脂肪变的发生和发展。     

Hepatic (dys-)function during inflammation

It is an understatement to say that the liver is an important organ. Each of the liver cells goes through thousands of complex biochemical interactions that influence all of the other organs in the body. Since the liver is involved with almost all biochemical processes it is no wonder that there are many different diseases that will affect it. A process known to impair liver function, including hepatic drug metabolism, is an infection induced inflammatory response. Infection induced alterations in liver function involve various cell types and their continuous cross-talk, as well as several circulating or locally secreted inflammatory mediators. Three main hepatic cell types contribute to the liver response during inflammation: hepatocytes, Kupffer cells and sinusoidal endothelial cells. In addition, activated neutrophils, which are also recruited in the liver and produce potentially destructive enzymes and oxygen-derived radicals, may further enhance liver injury. This review will focus on the pathway by which Kupffer cells and hepatocytes are activated and how this affects liver function, in particular hepatic drug metabolism.