酒精性与非酒精性脂肪性肝病

脂肪性肝病(FLD)根据有无过量饮酒史,分为酒精性肝病(ALD)和非酒精性脂肪性肝病(NAFLD)两大类。两者享有FLD的许多共性特征,但又各有其独特之处。 1.酒精性与非酒精性FLD的异同:NAFLD的肝组织学改变与ALD相似,包括单纯性脂肪肝、脂肪性肝炎及肝硬化。我国及日本学者认为ALD还应包括轻症ALD、酒精性重型肝炎及酒精性肝纤维化,事实上NAFLD均有其相对应的临床病理类     

DKK3在非酒精性脂肪性肝病的作用研究

目的探讨Dickkopf-3(DKK3)在小鼠非酒精性脂肪性肝病(NAFLD)形成中的意义。方法采用高脂饮食喂养C57BL/6雄性小鼠来构建NAFLD模型,通过检测肝功能、糖代谢变化、肝脏组织中脂质含量及肝脏病理学变化评估NAFLD模型是否成功;并用Western印迹方法检测肝脏组织中DKK3蛋白变化情况。结果高脂饮食组小鼠NAFLD相关指标均较对照组升高,差异有统计学意义(P0.05)。高脂饮食组小鼠肝脏中DKK3蛋白表达量较对照组明显下降,定量分析比较差异有统计学意义(P0.05)。结论DKK3在NAFLD小鼠肝组织中表达明显下降,提示DKK3涉及NAFLD的发生发展过程,并可能发挥一定的作用。     

非酒精性脂肪性肝病研究新进展

非酒精性脂肪性肝病( non- alcoholic fatty liver disease,NAFLD)是指除外酒精和其他明确的肝损害因素所致的,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,包括单纯性脂肪性肝病以及由其演变的脂肪性肝炎和肝硬化.NAFLD是21世纪全球重要的公共健康问题之一,也是常见的慢性肝病.     

非酒精性脂肪性肝病治疗进展

非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)已成为目前全球最主要的慢性肝病病因,是当前研究的热点问题,其预防和治疗也成了研究的重点和难点,目前尚无批准上市的特异性药物及明确的治疗方案,本文针对NAFLD的相关治疗及新兴靶向药物作一概述,给临床医师提供参考。     

非酒精性脂肪性肝病小鼠模型的研究进展

非酒精性脂肪性肝病(Non-alcoholic fatty liver disease,NAFLD)是在排除过量饮酒的情况下包括肝脏脂肪样变性、非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)、非酒精性脂肪性肝硬化在内的一组肝脏疾病.许多文献表明NAFLD与胰岛素抵抗密切相关[1],众多学者将其认为是代谢综合征的肝脏表现[2].NAFLD动物模型主要可以分为两大类:一类是由相关基因变异引起的遗传性模型;一类是由饮食或药物引起的获得性模型.近年来,遗传性与获得性相结合的模型进一步缩小了与人类NAFLD的差距.其中,小鼠模型被广泛应用于NAFLD的研究.笔者将就当前NAFLD小鼠模型的最新进展作一综述.     

非酒精性脂肪性肝病治疗进展

非酒精性脂肪性肝病无特效治疗方法,目前以生活方式调节为基础,必要时辅以药物治疗。本文从生活方式调节和药物治疗两方面回顾近年来的治疗研究进展。     

非酒精性脂肪性肝病治疗策略

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肪变为主要特征的临床病理综合征,包括单纯性脂肪肝以及由其演变的非酒精性脂肪性肝炎（NASH）和肝硬化。在欧美等发达国家,NAFLD发病率可达到20％～30％,在亚太地区成人NAFLD患病率亦达到12％～24％,而且目前仍呈上升趋势。     

美国非酒精性脂肪性肝病诊疗指南简介

2012年2月22日,美国肝脏病学会、美国胃肠病学院和美国胃肠病学会共同起草了《非酒精性脂肪性肝病诊疗指南》,并于2012年4月6日全文在《Hepatology》杂志在线发表。我们将推荐意见翻译成中文（括号内的“1或2”为推荐强度,“A、B或C”为证据的等级或质量）,供大家学习参考。     

巨噬细胞在非酒精性脂肪性肝病中的作用

随着生活水平的提高,非酒精性脂肪性肝病(NAFLD)发病率逐年升高并且趋于年轻化,但其具体发病机制尚未明确。巨噬细胞作为参与NAFLD发病的重要细胞之一,一直广受关注。针对肝脏巨噬细胞的来源及分类、巨噬细胞在NAFLD肝脏炎症中的作用和其活化的机制、靶向巨噬细胞药物进行阐述,旨在为临床治疗NAFLD提供参考。     

吡格列酮对SD大鼠非酒精性脂肪肝病形成的预防作用及其机制

目的:探讨吡格列酮(pioglitazone,PIO)对SD大鼠非酒精性脂肪肝病(non-alcoholic fatty liverdisease,NAFLD)形成的干预作用及机制.方法:♂SD大鼠72只,随机分为正常饮食组(NG)、高脂饮食组(HG)和PIO干预组(PIOG)各24只.PIOG喂饲高脂饲料,并同时予PIO药物灌胃8 wk.正糖高胰岛素钳夹实验检测IR水平,放免法和全自动生化仪检测血清生化指标,RT-PCR检测过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptorγ,PPARγ)mRNA表达,Western blot检测肝组织c-Jun氨基末端激酶(c-Jun amino-terminalkinase 1,JNK1)和PPARγ蛋白表达.结果:HG大鼠GIR水平降低和JNK1蛋白表达增高,均呈明显时间依赖性(均P<0.05);8 wk末HG大鼠肝细胞出现明显脂肪变性,与NG相比,体质量、肝指数,TG、ALT、AST、FFAs、FINS、TNF-α水平明显增高,IR加重,JNK1蛋白表达明显升高,肝组织PPARγ表达明显降低(TG:1.23±0.08 vs 0.62±0.12,ALT:92.80±7.09 vs 51.34±8.12;AST:153.22±20.65 vs 119.26±13.61;FFAs:511.94±24.88vs 335.31±15.71;FINS:41.23±1.84 vs 22.65±2.25;TNF-α:1.02±0.12 vs 0.34±0.07,均P<0.05);而PIOG大鼠,上述各项指标均得到明显改善,但仍不能完全达到NG大鼠水平(均P<0.05).结论:PIO对于由高脂饮食诱导的NAFLD的形成及其他IR相关疾病有预防作用.     

Leptin in nonalcoholic fatty liver disease

Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition associated with obesity and insulin resistance (IR). Leptin plays a key role in the control of energy balance, and insulin sensitivity. In this study, we aimed to examine whether serum leptin levels correlate with insulin resistance, oxidative stress parameters and the severity of histological changes in NAFLD. Methods: Fifty-two patients (M/F: 28/24) with no alcohol intake and biopsy-proven diagnosis of NAFLD were studied. Serum leptin levels were measured by radioimmunoassay. HOMA (homeostasis model assessment) IR index was calculated. Comparisons between the patients with NAFLD and non-alcoholic steatohepatitis (NASH) were performed using the Student’s t test. Multivariate regression analysis and the area under the receiver operating characteristic (ROC) curve were used to identify the independent predictors for NASH. Results: We found no association between serum leptin, fasting insulin levels, and oxidative stress parameters. ROC curve and multiple regression analysis revealed no association between the severity of histological changes and serum leptin levels. During six months followed-up period only NASH group with elevated leptin levels had significant reductions of ALT and AST values (p = 0.03, and 0.005, respectively). Conclusion: Our findings show a preventive effect of leptin against progressive liver injury in NAFLD.     

Biomarkers in nonalcoholic fatty liver disease

BACKGROUND:

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition characterized by insulin resistance, type 2 diabetes and fat accumulation in the liver that may cause hepatic inflammation and progressive scarring leading to nonalcoholic steatohepatitis (NASH) and irreversible liver damage (cirrhosis). As a result, there has been increased recognition of the need to assess and closely monitor individuals for risk factors of components of NAFLD and NASH, as well as the severity of these conditions using biomarkers.

AIM:

To review the biomarkers used to diagnose and define the severity of NAFLD and NASH.

METHODS:

A comprehensive PubMed and Google Scholar literature search was performed using the terms “non-alcoholic fatty liver disease”, “non-alcoholic steatohepatitis”, as well as the name of each biomarker known to be used. Articles indexed between 2004 and 2014 were used. Each author read the publications separately and the results were discussed.

RESULTS:

Biomarkers offer a potential prognostic or diagnostic indicator for disease manifestation, progression or both. Serum biomarkers, including total cholesterol, triglycerides, insulin resistance and C-peptide, have been used for many years. Emerging biomarkers, such as apolipoprotein A1, apolipoprotein B, leptin, adiponectin, free fatty acids, ghrelin and tumour necrosis factor-alpha, have been proposed as tools that could provide valuable complementary information to that obtained from traditional biomarkers. Moreover, markers of cell death and mitochondrial dysfunction (cytokeratins) represent powerful predictors of risk. For biomarkers to be clinically useful in accurately diagnosing and treating disorders, age-specific reference intervals that account for differences in sex and ethnic origin are a necessity.

CONCLUSIONS:

The present review attempts to provide a comprehensive analysis of the emerging risk biomarkers of NAFLD and NASH, and to use the clinical significance and analytical considerations of each biomarker pointing out sentinel features of disease progression.     

Mitochondria in nonalcoholic fatty liver disease

Nonalcoholic fatty liver (NAFL) is associated with fundamental issues of fat metabolism and insulin resistance. These abnormalities have been linked to impairment of ATP homeostasis, and a growing body of literature has reported mitochondrial abnormalities in various forms of hepatic steatosis. The changes are evident as structural abnormalities, including greatly increased size and the development of crystalline inclusions, and are usually regarded as pathologic, reflecting either a protective or degenerative response to injury. Although the relationships between structural changes,decreased mitochondrial function, and disease states are becoming clearer, the molecular basis for the perturbations is not well understood.Oxidative damage is the most likely causative process and may result in alterations of mitochondrial DNA (mtDNA), stimulated apoptotic pathways, and increased propensity for necrosis.Overall mitochondrial health likely depends on multiple factors including the integrity of the mtDNA, the composition of cellular lipids, lipoprotein trafficking, the balance of pro- and antioxidant factors, and the metabolic demands placed on the liver. Mitochondrial dysfunction may play a role in numerous clinical conditions associated with NAFL, such as hepatocellular carcinoma, lipodystrophy,age-related insulin resistance, gut dysmotility, cryptogenic cirrhosis, a mild form of gaze palsy, and possibly other more severe neurodegenerative diseases. The prominent role of mitochondrial dysfunction in NAFL provides a new and exciting paradigm in which to view this disorder, its complications, and potential dietary and pharmacologic intervention.     

Theacrine protects against nonalcoholic fatty liver disease by regulating acylcarnitine metabolism

ObjectiveAcylcarnitine metabolism disorder contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). There are, however, few ideal medications for NAFLD, which work by targeting acylcarnitine metabolism. The aim of this study was to investigate the protective effects of theacrine, a rare purine alkaloid isolated from Camellia assamica var. kucha, against acylcarnitine metabolism disorder in NAFLD.MethodsThe pharmacological activities of theacrine were studied using high-fat diet (HFD)-fed ApoE−/− and C57BL/6J mice models. Oleate-treated HepG2 and L-02 cells were used to investigate the molecular mechanism of theacrine on acylcarnitine metabolism. The target of theacrine was confirmed in vitro as the blockade of sirtuin 3 (SIRT3) and protein kinase A.ResultsTheacrine inhibits hepatic steatosis and liver inflammation and improves energy expenditure in HFD-fed mice. Theacrine ameliorates acylcarnitine metabolism disorder in HFD-fed mice and oleate-treated hepatocytes by improving fatty acid oxidation. The underlying mechanism involves theacrine's activation of the mitochondrial deacetylase SIRT3 and consequently, the increased activity of long-chain acyl coenzyme A dehydrogenase (LCAD) through deacetylation.ConclusionTheacrine promotes acylcarnitine metabolism in NAFLD through the SIRT3/LCAD signaling pathway. The target of theacrine's activities on NAFLD is identified as SIRT3.     

Genes and nonalcoholic fatty liver disease

Whereas most individuals with nonalcoholic fatty liver disease (NAFLD) will have steatosis, only a minority will ever develop progressive disease. Family studies and interethnic variations in susceptibility suggest that genetic factors may be important in determining disease risk. Although no genetic associations with advanced NAFLD have been replicated in large studies, preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, tumor necrosis factor-α, transforming growth factor-β, and angiotensinogen may be associated with steatohepatitis and/or fibrosis. With the advent of high-throughput gene analyses and the reduced cost of whole genomewide scans, it seems likely that genes contributing to inherited susceptibility to this common disease will be identified in the near future.     

Treatment of nonalcoholic fatty liver disease

Opinion statement Nonalcoholic fatty liver disease (NAFLD) is very common in the United States, and in some patients it may lead to cirrhosis, liver failure, and liver cancer. NAFLD encompasses a spectrum of liver injury, ranging from steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. Nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD, histologically comprises steatosis, balloon degeneration, inflammation, and fibrosis in varying degrees. It is generally believed that simple steatosis is benign with minimal risk of progression, whereas NASH is progressive and can lead to cirrhosis. The commonly associated risk factors for NAFLD include obesity, hyperlipidemia, and diabetes mellitus. The pathogenesis of NAFLD and NASH is not fully known; however, current evidence suggests that insulin resistance and lipid peroxidation play a role in the pathogenesis of this condition. Currently, there are no proven effective therapies available for the treatment of NASH. Although there are numerous studies that have explored various treatments for NASH, these generally consist of small numbers of patients with suboptimal endpoints. Treatment strategies for NAFLD and NASH can be broadly divided into 1) treatment or control of underlying risk factors such as hyperlipidemia, diabetes mellitus, and obesity; and 2) specific pharmacologic therapy such as insulin sensitizers, antioxidants, or cytoprotective agents. Newer thiazolidinediones, such as rosiglitazone and pioglitazone, have shown promise in the treatment of NASH in pilot studies. However, these agents should not be used in clinical practice until their efficacy and safety are firmly established in larger studies. Despite encouraging initial studies, the recently completed multicenter, randomized, controlled trial failed to show any efficacy for ursodeoxycholic acid in the treatment of NASH. Other agents, such as vitamin E, betaine, probucol, and atorvastatin, have been explored as therapeutic agents for NASH. However, none of these studies have shown convincingly their utility in the treatment of NASH. Attempts to identify optimal therapy for patients with NASH are being vigorously pursued by the research community and important advances are expected within next several years. Until then, subjects should be advised to avoid alcohol, lose weight, and exercise regularly, and meticulous attention should be paid to the control of their risk factors such as diabetes and hyperlipidemia.     

Update on nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease is now recognized as the most common liver disease in the United States, with a prevalence of approximately 5% in the general population and up to 25% to 75% in patients with obesity and type II diabetes mellitus. Nonalcoholic fatty liver disease is a clinicopathologic syndrome with a wide spectrum of histologic abnormalities and clinical outcomes. Hepatic steatosis has a benign clinical course. In contrast, nonalcoholic steatohepatitis (NASH) may progress to cirrhosis and liver-related death in 25% and 10% of patients, respectively. Cases occur most commonly in obese, middle-aged women with diabetes. However, NASH may also occur in children and normal-weight men with normal glucose and lipid metabolism. The pathophysiology involves two steps. The first is insulin resistance, which causes steatosis. The second is oxidative stress, which produces lipid peroxidation and activates inflammatory cytokines resulting in NASH. Liver biopsy provides prognostic information and identifies NASH patients who may benefit from therapy. Treatment consists of managing the comorbidities: obesity, diabetes, and hyperlipidemia. Although antioxidant therapy with vitamin E is often used, ursodeoxycholic acid is the only drug that has shown benefit and is the most promising of the drugs currently being investigated. Future therapies will depend on a greater understanding of the pathophysiology and should focus on diminishing fibrosis.     

Genetic influences in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a metabolic liver disease with widely variable phenotypes extending from simple steatosis, through nonalcoholic steatohepatitis (NASH) to cirrhosis and hepatocellular carcinoma. Inevitably, this reflects the interplay of well-recognized environmental factors and disease associations such as obesity and insulin resistance with host genetic factors, which are polygenic or complex in nature. Most of the observed phenotypic variability will probably be explained by variations in single nucleotide polymorphism frequency, although knowledge of the effect of most polymorphisms on biologic function is currently limited. Several observational studies of kindred with NASH suggest a genetic contribution. Most data characterizing genetic variation in different NAFLD phenotypes is derived from case-control association studies involving putative candidate genes. These candidate genes have been selected largely based upon the "two-hit hypothesis" of the pathogenesis of NAFLD, although other hypothesis-independent approaches can also be informative in gene selection. Thus far, candidate gene association studies have had significant limitations such as small cohort sizes and poor reproducibility. Rapid technologic developments are increasing the capability of detecting genetic variation. Identification of the genetic contribution to NAFLD will inform theories of disease pathogenesis and progression and ultimately improve management.