血清脂联素在非酒精性脂肪肝发病中的意义

既往认为非酒精性脂肪性肝病(NAFLD)是一种良性可逆性病变,但随着对其研究的深入,目前普遍认为NAFLD不光是良性病变,它同样可进展成包括肝纤维化、肝硬化甚至引起肝衰竭、肝癌等严重肝病.Day提出的"二次打击"学说认为初次打击主要为胰岛素抵抗促使肝脏甘油三酯蓄积,导致肝细胞对内外源性损害因子的敏感性增强.而炎症因子产生,游离脂肪酸增多,肝细胞内TG氧化增多,肝细胞能量储备不足,内毒素、铁蓄积等因素则通过诱发氧化应激导致脂质过氧化损伤,对肝脏进行第二次打击.     

非酒精性脂肪肝的药物治疗现状

非酒精性脂肪肝指肝脏组织病理学变化与酒精性脂肪肝相似,但无饮酒史的一种获得性代谢疾病。非酒精性脂肪肝作为肝硬化和终末期肝病病因之一日益受到重视 ,但其确切病因尚不清楚 ,至今也尚无完全有效的药物治疗措施[1]。关于其发病机制Day[2]等提出的二次打击学说影响较大 :第一次打击为各种原因导致肝脏脂肪沉积,尤其是游离脂肪酸和甘油三酯 ,肝脏脂肪动态平衡被破坏 ,游离脂肪酸被不断运送到肝脏内 ,而肝脏对脂肪酸 β-氧化能力下降 ,胰岛素抵抗和脂肪代谢失衡是脂肪肝形成主要启动因素 ,胰岛素抵抗导致脂蛋白脂肪酶基因过度表达 ,在肝脏…     

肿瘤坏死因子-α在非酒精性脂肪性肝病中的作用机制及其综合治疗

非酒精性脂肪性肝病（NAFLD）是指除外酒精和其他明确的损肝因素所致的,以弥漫性肝细胞大泡性脂变为主要特征的临床病理综合征,包括单纯性脂肪肝（SS）、非酒精性脂肪性肝炎（NASH）和脂肪性肝硬化（NAFH）3种类型。近年来由于人们生活方式及饮食结构等的改变,NAFLD的患病率日益增高,其对公众健康的危害性受到普遍关注。目前NAFLD的发病机制尚未完全阐明,广为接受的是Day等[1]提出的“二次打击”学说。     

非酒精性脂肪性肝病的综合治疗

非酒精性脂肪性肝病(NAFLD)是代谢综合征在肝脏的表现,其疾病谱包括非酒精性单纯性脂肪肝、非酒精性脂肪性肝炎(NASH)和肝硬化.其治疗应为综合性下预,包括通过调整生活方式、药物及手术治疗等方法改善胰岛素抵抗,减少易致肝脏损伤的因素,必要时可应用保肝抗炎药物,终末期NAFLD患者需行肝移植术.     

白藜芦醇对高尿酸介导的非酒精性脂肪肝大鼠血脂及肝组织脂肪变的影响

<正>非酒精性脂肪性肝病(NAFLD)是目前最常见的肝脏问题,可能会进展到其他肝脏疾病,如非酒精性脂肪性肝炎、肝纤维化、肝硬化,甚或肝癌。NAFLD是多种因素导致的一系列肝细胞脂肪浸润~([1]),其中饮食条件不容忽视。近期研究表明,血清尿酸升高与脂肪肝密切相关~([2,3]),并影响其严重程度~([4])。目前尚没有药物治疗证实对NAFLD有确切疗效。白藜芦醇(resveratrol,Res),化学名为3,4,5-三羟基二苯乙烯,是     

非酒精性脂肪性肝病发病机制及治疗进展

近年来,非酒精性脂肪性肝病(Nonalcoholic fatty liver disease,NAFLD)发病率在世界范围内逐渐上升,在我国是仅次于病毒性肝炎、酒精性脂肪性肝病的导致肝硬化的主要病因之一。其发病机制尚不清楚,目前较为公认的机制为"二次打击"学说,第一次打击为胰岛素抵抗,脂质代谢紊乱导致肝细胞内脂质过度沉积,三酰甘油增多;第二次打击是肝细胞内氧化应激及脂质过氧化,是发展为NASH、肝硬化甚至肝癌的关键。近年来,对胰岛素增敏剂治疗NAFLD的研究较多,而关于降脂药的研究则少见。本综述从NAFLD的概述、发病机理、降血脂药的作用等方面进行阐述。     

降脂益肝冲剂对非酒精性脂肪肝大鼠凋亡调控基因的影响

<正>目前在非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)的发病机制中,以"二次打击"学说得到普遍公认。然而随着对细胞凋亡的研究,不断有证据表明,在NAFLD中,肝细胞凋亡可能是单纯非酒精性脂肪肝发展为非酒精性     

2型糖尿病合并非酒精性脂肪肝的治疗

非酒精性脂肪肝(NAFLD)是指在没有大量酒精摄入的前提下,肝脏出现以弥漫性肝细胞大泡性脂肪变为主要特征的临床病理综合征.虽然NAFLD是一组良性病变,但NAFLD可以发展为非酒精性脂肪性肝炎(NASH)、肝硬化,部分患者甚至发展为肝细胞性肝癌.NAFLD与肥胖、糖尿病、血脂异常、高血压和胰岛素抵抗(IR)等因素密切相关,是代谢综合征在肝脏的表现,也是心血管疾病(CVD)的独立危险因素.     

从典型病例谈NAFLD的诊断和治疗

非酒精性脂肪性肝病（NAFLD）是指除外过量饮酒和其他明确的损肝因素所致的肝细胞内脂肪沉积,其疾病谱包括非酒精性单纯性脂肪肝（nonalcoholic simple fatty liver,NAFL）、非酒精性脂肪性肝炎（nonalcoholic steatohepatitis,NASH）及其相关肝硬化和肝细胞癌。非酒精性脂肪性肝病的发病与肥胖、糖尿病、代谢综合征密切相关,被认为是代谢综合征在肝脏的表现。     

非酒精性脂肪性肝病合并高血压的影响因素分析

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是一种常见慢性肝病,包括非酒精性单纯性脂肪肝、非酒精性脂肪性肝炎及脂肪性肝炎相关的肝硬化.NAFLD发病率逐年增高,其病程中,往往并发代谢综合征.笔者对NAFLD并发高血压患者的临床生化指标进行分析,探讨其危险因素,为临床防治提供依据.     

Advances in the understanding and treatment of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a well recognised form of chronic liver disease that has recently gained greater recognition. Originally described in the late 1950s, NAFLD is currently considered the leading cause of abnormal liver enzyme levels in the US, closely paralleling the increase in obesity and diabetes mellitus. NAFLD has a worldwide distribution, affecting both adults and children, and typically is seen in association with obesity, diabetes, hypertension and hypertriglyceridaemia. Most patients are asymptomatic and usually present with mild elevations in aminotransferases. The natural history of NAFLD is not clearly defined but progression to cirrhosis and end-stage liver disease is well recognised in some patients. The accumulation of hepatic steatosis is thought to occur initially, primarily through hepatic and peripheral insulin resistance, which leads to altered glucose and free fatty acid metabolism. The progression from simple fatty liver to more severe forms of NAFLD (nonalcoholic steatohepatitis and cirrhosis) is much less clear but evidence suggests that oxidative stress may preferentially enhance proinflammatory cytokines, which leads to cellular adaptations and dysfunction followed by development of inflammation, necrosis and fibrosis. Therapeutic modalities remain limited and are largely focused on correcting the underlying insulin resistance or reducing oxidative stress. However, at the present time, there are several limitations to the current potential therapies, mainly because of the lack of large-scale, prospective, randomised studies, as well as clearly defined histological endpoints. Ultimately, the future for potential therapeutic modalities to treat this disease are quite promising, but further research is needed to clearly demonstrate which therapy or therapies will be effective at eliminating fatty liver disease and its potential complications.     

非酒精性脂肪肝与钙稳态关系的研究进展

钙离子（Ca²⁺）是细胞内重要的第二信使,其主要储存在内质网和线粒体中,参与调控细胞多种生理功能及维持内质网、线粒体功能。内质网和线粒体对钙离子的摄取与释放直接影响胞内钙离子水平的变化,继而影响细胞正常生理功能。病理条件下,细胞内钙离子稳态失衡,可引发细胞生理功能异常并进一步影响内质网、线粒体功能。非酒精性脂肪肝（NAFLD）是临床常见病和多发病,其主要病理特征是：肝脏脂肪样变性、内质网应激、线粒体损伤和非特异性炎性反应等。其中持续的内质网应激及线粒体功能障碍是NAFLD发生发展的重要诱因。而细胞内钙稳态的变化可直接导致内质网及线粒体功能异常,继而影响NAFLD的发生发展。本文主要从钙稳态的主要影响因素以及钙稳态变化与NAFLD的关系两方面进行阐述,为寻求和研发防治NAFLD的药物提供新的方向。     

The endoplasmic reticulum as a potential therapeutic target in nonalcoholic fatty liver disease

The endoplasmic reticulum (ER) has emerged as a key to understanding the development and consequences of hepatic fat accumulation in nonalcoholic fatty liver disease (NAFLD). An essential function of this organelle is the proper assembly of proteins that are destined for intracellular organelles and the cell surface. Recent evidence suggests that chemical chaperones that enhance the functional capacity of the ER improve liver function in obesity and NAFLD. These chaperones may therefore provide a novel potential therapeutic strategy in NAFLD.     

Methodologies for investigating natural medicines for the treatment of nonalcoholic fatty liver disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is emerging as a prominent condition in Western countries. In this review we describe the characteristics and current treatments of NAFLD and discuss opportunities for developing new therapeutic management approaches, with a particular emphasis on development of animal studies and in vitro assays for identification of components of natural product medicines. The main manifestation of NAFLD is hepatic lipid accumulation in the form of lipid droplets (LDs), known as hepatic steatosis (fatty liver). Current treatments for NAFLD generally aim to reduce triglyceride (TG) accumulation, often utilizing thiazolidinedines (TZDs) and fibrates, which are known to lower TG levels in hyperlipidemia, diabetes and metabolic syndrome. Both of these compounds act through activation of nuclear receptors of the Peroxisome Proliferator-Activated Receptor (PPAR) family, thereby activating genes involved in triglyceride metabolism. Thus treatment using natural PPAR α and PPAR γ ligands, such as polyunsaturated fatty acids (PUFA), has also been considered. Alternatively, natural medicines for the treatment of NAFLD have a long and successful history of controlling disease without prominent side effects. However, active compounds in natural medicine responsible for lowering hepatic TG levels are yet poorly characterized. This points to the need for medium-high throughput screening assays to identify active components within natural herbs. As outlined in this review, the quantification of the size and number of lipid droplets could provide an opportunity to screen compound libraries derived from natural medicine for their potential to reduce NAFLD.     

Novel role of NPC1L1 in the regulation of hepatic metabolism: potential contribution of ezetimibe in NAFLD/NASH treatment

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and also in other parts of the world. NAFLD encompasses a histological spectrum ranging from simple steatosis to steatohepatitis, advanced fibrosis and inflammatory changes. It frequently occurs with features of the metabolic syndrome including obesity, type 2 diabetes mellitus, dyslipidemia and hypertension. In fact, the metabolic syndrome is a strong predictor of NAFLD. Recently, Niemann-Pick C1-like 1 (NPC1L1) has been shown to play a pivotal role in cholesterol absorption. Unlike mouse NPC1L1 protein, predominantly expressed in the intestines, human and rat NPC1L1 is also abundantly expressed in the liver. Though the exact functions of hepatic NPC1L1 remain unknown, NPC1L1 may facilitate the hepatic accumulation of cholesterol. This raises a potential possibility that ezetimibe may improve fatty liver formation. In this review, potential role of lipid metabolism in NAFLD and its possible modulation through NPC1L1 blockade is discussed.     

Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis

Non-alcoholic fatty liver disease (NAFLD) is characterized by the aberrant accumulation of triglycerides in hepatocytes in the absence of significant alcohol consumption, viral infection or other specific causes of liver disease. NAFLD has become a burgeoning health problem both worldwide and in China, but its pathogenesis remains poorly understood. Farnesoid X receptor (FXR), a member of the nuclear receptor (NR) superfamily, has been demonstrated to be the primary sensor for endogenous bile acids, and play a crucial role in hepatic triglyceride homeostasis. Deciphering the synergistic contributions of FXR to triglyceride metabolism is critical for discovering therapeutic agents in the treatment of NAFLD and hypertriglyceridemia.     

Endoplasmic reticulum stress is involved in hepatic SREBP-1c activation and lipid accumulation in fructose-fed mice

A link between fructose drinking and nonalcoholic fatty liver disease (NAFLD) has been demonstrated in human and rodent animals. The aim of the present study was to investigate whether endoplasmic reticulum (ER) stress is mediated in the development of fructose-induced NAFLD. Female CD-1 mice were fed with 30% fructose solution for eight weeks. Hepatic lipid accumulation was assessed. Hepatic nuclear sterol regulatory element-binding protein (SREBP)-1c was measured. Results showed that hepatic SREBP-1c was activated in mice fed with fructose solution. Fatty acid synthase (fas) and acetyl-CoA carboxylase (acc), two target genes of SREBP-1c, were up-regulated. Fructose-evoked hepatic SREBP-1c activation seemed to be associated with insulin-induced gene (Insig)-1 depletion. An ER stress and unfolded protein response (UPR), as determined by an increased glucose-regulated protein (GRP78) expression and an increased eIF2α and PERK phosphorylation, were observed in liver of mice fed with fructose solution. Phenylbutyric acid (PBA), an ER chemical chaperone, not only significantly attenuated ER stress, but also alleviated fructose-induced hepatic Insig-1 depletion. PBA inhibited fructose-evoked hepatic SREBP-1c activation and the expression of SREBP-1c target genes, and protected against hepatic lipid accumulation. In conclusion, ER stress contributes, at least in part, to hepatic SREBP-1c activation and lipid accumulation in fructose-evoked NAFLD.     

Current treatment strategies for non-alcoholic fatty liver disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common cause of chronic liver disease worldwide. NAFLD is a clinicopathologic syndrome ranging from simple steatosis, which is relatively benign, to the more severe form known as nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, liver failure, and hepatocellular carcinoma. NAFLD is associated with significant liver related morbidity and mortality, and its underlying pathophysiology is thought to result from a multiple hit process. The initial insult is the accumulation of hepatic fat secondary to insulin resistance. In the setting of hepatic steatosis, the second hit can be caused by reactive oxygen species, inflammatory cytokines, and adipokines. Several therapeutic modalities that target these mechanisms are under investigation, but no proven treatment has yet emerged. Insulin sensitizers such as thiazolidinediones and metformin show promise, and several studies have explored the role of lipid lowering agents, antioxidants, and cytoprotective agents. Novel agents such as anti-obesity drugs, selective cannabinoid-1 receptor blockers, and dual PPAR alpha and gamma agonists are also under investigation. Unfortunately, data on the long-term safety and efficacy of these agents and their impact on liver related histologic outcomes are currently lacking. NAFLD treatment currently focuses on reducing metabolic risk factors, with the mainstay of therapy focusing on life-style modifications such as gradual weight loss through diet and regular exercise.     

Acanthoic acid modulates lipogenesis in nonalcoholic fatty liver disease via FXR/LXRs-dependent manner

OBJECTIVE To reveal the effect and mechanism of acanthoic acid(AA) on nonalcoholic fatty liver disease(NAFLD) associated with lipid accumulation by activating Farnesoid X receptor(FXR) and liver X receptors(LXRs) signaling. METHODS C57 BL/6 mice were received a modified Lieber-De Carli diet with 71%high-fat(L-D) and treated with AA(20 and 40 mg·kg~(-1)) or equal volume of saline for 12 weeks. The regulation of AA on lipid accumulation was also detected in pro-steatotic stimulated AML12 cells with palmitic acid(PA).RESULTS When L-D diet-fed mice were treated with AA, loss in body mass, liver index, and liver lipid droplet were observed along with reduced triglyceride(TG) and serum transaminase. Furthermore, AA decreased sterol regulatory element binding protein 1(SREBP-1) and target genes expression, regulated PPARα and PPARγ expressions, ameliorated hepatic fibrosis markers, enhanced hepatic FXR and LXR, and regulated AMPK-LKB1 and SIRT1 signaling pathway. Moreover, AA attenuated lipid accumulation via FXR and LXR activation in steatotic AML-12 cells, which was confirmed by guggulsterones(FXR antagonist) or GW3965(LXR agonist). CONCLUSION Activation of FXR and LXR signaling caused by AA might increase AMPK-SIRT1 signaling and then contribute to modulating lipid accumulation and fatty acid synthesis, which suggested that activated FXR-LXR axis by AA represented an effective strategy for relieving NAFLD.