肠道菌群与非酒精性脂肪肝相关性的研究进展

非酒精性脂肪肝(NAFLD)是我国最常见的慢性肝病之一,为非酒精性因素所致的肝细胞脂肪变为特征的综合征,包括单纯性脂肪肝(SFL)、非酒精性脂肪性肝炎(NASH)及其相关肝硬化和肝细胞癌(HCC)。人体肠道中的各种菌群发挥着不同的病理生理作用,与许多疾病密切相关,肠道菌群可以通过"肠-肝轴"影响NAFLD的发生发展,"二次打击"学说很好地解释了NAFLD的发病机制及其与肠道菌群的关系。益生元、益生菌可以很好地调节肠道菌群,与抗生素和手术相比更加廉价、无害、安全,有望成为预防和治疗NAFLD的新方法。本研究对肠道菌群与NAFLD相关性的研究进展加以综述。     

2型糖尿病并发非酒精性脂肪性肝病发病机制的研究进展

随着2型糖尿病(type 2 diabetes,T2DM)患者人数的不断增加,T2DM已成为现代社会影响人们生活质量的沉重负担.T2DM的主要危害为其慢性并发症,除已知的心脑血管、肾脏、视网膜等病变外,非酒精性脂肪肝(nonalcoholic fatty liver disease,NAFLD)也是其常见并发症之一.T2DM与NAFLD密切相关,非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)是T2DM患者终末期肝病的最主要原因,并且促进心血管疾病的发生.T2DM和NAFLD相互影响,产生严重后果,因此对二者发病机制的研究也越来越受到重视.本文将就2型糖尿病并发非酒精性脂肪性肝病发病机制的研究进展做一综述.     

非酒精性脂肪肝发病机制和治疗的研究进展

非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)已成为全球最常见肝病之一,其发病率仍然有继续增加的趋势。NAFLD是一类包含单纯性脂肪肝、非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NASH)等疾病的临床病理综合征,并可能进一步进展为肝硬化、肝衰竭和肝细胞性肝癌,威胁人类健康。目前NAFLD的发病机制尚不完全清楚,并且尚没有理想的有效治疗药物。该文主要就NAFLD的发病机制和治疗的研究进展进行综述,为NAFLD的基础研究和临床治疗提供相关的参考。     

NAFLD患者肠粘膜机械屏障损伤的研究

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是慢性肝损伤的主要病因之一。据估计,大约有20%的成人有非酒精性脂肪性肝病,2%-3%发展成非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)。NASH是NAFLD的渐进形式,并可能导致肝硬化和肝细胞癌。NAFLD不仅增加了肝病患者死亡率,作为代谢综合征,还增加了肥胖、2型糖尿病及高脂血症的发病率。肌球蛋白轻链激酶(MLCK)是细胞收缩的关键酶,可使肌球蛋白轻链磷酸化(MLC),促使肌动蛋白收缩,破坏细胞间的紧密连接蛋白,使细胞骨架收缩,进而使肠上皮通透性增加,肠粘膜机械屏障遭到破坏,致使NAFLD的病情进一步发展。MLCK在NAFLD的发生及发展中起着重要作用。NAFLD严重威胁人类健康,影响人们的生活质量及生存质量。为NAFLD患者寻找崭新的治疗方法是极其必要的。     

模拟人类非酒精性肝病的小鼠模型

<正>非酒精性脂肪肝病(nonalcoholic fatty liver disease,NAFLD)为当前全球最常见慢性肝病,且呈低龄化趋势,其俗称为"脂肪肝";其病理特征,为肝细胞脂肪变性;其病因,可排除酗酒史及其他肝病因素;其发病率高,西方国家达15%~30%,我国达15%;该病初期,为单纯性脂肪肝(nonalcoholic simple fatty liver,NAFL)病情较稳定;然而,如发展到脂肪性肝炎(nonalcoholic steatohepatitis,NASH),则可进一步恶变为肝硬化、肝癌;脂肪性肝炎患病10~15年肝硬化率达15%~25%,其中约30%~     

固醇调节元件结合蛋白2信号通路与非酒精性脂肪性肝病北大核心CSCD

非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)是以肝细胞内甘油三酯和胆固醇等脂毒性脂肪过度沉积为主要特征的一种临床获得性代谢综合征。最新研究表明,NAFLD向非酒精性脂肪肝炎(NASH)进展时,肝内胆固醇积累可能较甘油三酯更具有细胞毒性风险。固醇调节元件结合蛋白2(sterol regulatory element-binding protein 2,SREBP2)是脂质代谢重要的核转录因子之一,主要调控胆固醇的生物合成和体内平衡。SREBP2及其靶基因调控的胆固醇异常是引起非酒精性脂肪肝病发生发展的重要因素之一。因此,认识SREBP2信号通路中,上下游各因素的表达调控作用与NAFLD发病机制之间关系,就显得非常重要。本文总结了受SREBP2调控表达的靶基因的特点,着重介绍SREBP2调控胆固醇体内合成与平衡的信号通路与NAFLD发病机制之间关系,为研究和指导治疗NAFLD及其代谢性疾病提供新的思路。     

非酒精性脂肪肝病形成机制:补体和线粒体在其形成中的作用

非酒精性脂肪肝病(nonalcoholic fatty liver disease,NAFLD)作为一种流行性代谢疾病,一直是研究热点之一.NAFLD的形成涉及线粒体功能障碍、胰岛素抵抗、氧化应激、炎症反应等机制,而线粒体与补体在其中占据重要位置.然而,线粒体与补体在NAFLD形成过程中的内在关联及协同作用目前尚不十分...     

GSDMD调控非酒精性脂肪肝中细胞焦亡的研究进展

细胞焦亡是一种炎症相关的细胞程序性死亡方式,由胱天蛋白酶(caspase)和炎性小体介导,最终依赖gasdermin家族成员gasdermin D(GSDMD)执行。细胞焦亡的发生伴随着细胞内炎性因子的外泄及免疫细胞的活化,因此与炎症反应的发生密切相关。非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)是一种病因不明的慢性肝病,如果缺乏有效的干预手段,脂肪变性会逐渐进展至炎症、纤维化,最终发展至肝硬化。GSDMD 介导的细胞焦亡在非酒精性脂肪性肝病的发病过程中扮演重要角色,不仅会导致肝细胞死亡,还会加重炎症反应和纤维化的进程。抑制GSDMD 的功能从而减少细胞焦亡能够有效地缓解NAFLD 中的脂质堆积和炎症反应,这将为NAFLD 的治疗开辟一个新的研究方向。本文将概述GSDMD 介导的细胞焦亡的分子机制,并关注GSDMD 和细胞焦亡在NAFLD 发病机制及治疗方面的研究进展,为NAFLD 的诊治提供新思路。     

天然药物对非酒精性脂肪肝的作用

非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)是世界上最常见的慢性肝病,是由环境、遗传背景以及代谢应激之间相互作用产生的多因素疾病。所涉及到的机制复杂,目前已经证实的治疗NAFLD最有效的方法是,饮食干预和锻炼以减轻体重,尚未有专门用于治疗NAFLD的药物。大量的体内外实验证实,多种天然药物可以通过各种机制来干预NAFLD,且疗效显著。本文主要总结了近年来常用天然药物防治NAFLD的研究进展,为进一步的新药研发提供信息。     

基于生物信息学方法探讨非酒精性脂肪性肝炎免疫浸润特征及风险模型构建

非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)已成为严重影响患者生活质量和预期寿命的肝脏疾病,且发病机制复杂。为探讨免疫浸润在NASH发病机制中的作用,从高通量基因表达(gene expression omnibus, GEO)数据库中下载肝脏单纯性脂肪变性(simple steatosis, SS)、 NASH和健康受试者的数据集。使用R limma软件包对差异表达基因(differentially expressed genes, DEGs)进行筛选。通过功能注释和富集分析探讨DEGs的生物学功能。用无监督的一致性聚类及单样本基因集富集分析(single sample gene set enrichment analysis, ssGSEA)观察聚类模式所对应的免疫浸润类型。结果共获得1 569个DEGs,以及与NASH进展相关或不相关的两种修饰模式A、 B。模式B相较模式A对应较高的肝纤维化程度、小叶炎症程度、气球样变程度以及非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)活动度评分...     

Interaction of gut microbiota with dysregulation of bile acids in the pathogenesis of nonalcoholic fatty liver disease and potential therapeutic implications of probiotics

The intestinal microbiota is now recognised to play key roles in health due to its involvement in many aspects of human physiology. Disturbance in gut microbiota (dysbiosis) is thus associated with many diseases including nonalcoholic fatty liver disease (NAFLD) which includes nonalcoholic fatty liver and nonalcoholic steatohepatitis. The mechanisms for the effect of dysbiosis in NAFLD pathogenesis are not completely elucidated. Many explanations have been proposed to trigger dysbiosis, leading to NAFLD including inflammation, ethanol produced by the gut bacteria and lipotoxicity. Recently the roles of bile acids and nuclear receptors are highly regarded. It is well known that gut microbes produce enzymes that convert primary bile acids into secondary bile acids in the intestines. Several studies have demonstrated that disturbance of the intestinal microbiota leads to decreased synthesis of secondary bile acids, which in turn decreases activation of nuclear receptors such as farnesoid X receptor (FXR), pregnane X receptor, Takeda G-protein–coupled bile acid protein 5 and vitamin D receptor. These receptors are important in energy regulation and their dysregulation can cause NAFLD. Therefore, stimulation of nuclear receptors especially FXR has been extensively explored for the amelioration of NAFLD. However, paradoxical effects of nuclear receptor activation are a major problem for the clinical application of nuclear receptor stimuli. We further posit that microbiome restoration could be an alternative approach for the treatment of NAFLD. Several gut bacteria are now known to be involved in bile acid metabolism. It will be necessary to identify which one/ones is/are feasible. Careful selection of commensal bacteria for probiotics may lead to an effective therapy for NAFLD.     

Targeting the gut microbiota with resveratrol: a demonstration of novel evidence for the management of hepatic steatosis

Resveratrol is a natural polyphenol that has been reported to reduce the risk of obesity and nonalcoholic fatty liver disease (NAFLD). Recent evidence has demonstrated that the gut microbiota plays an important role in the protection against NAFLD and other metabolic diseases. The present study aimed to investigate the relationship between the gut microbiota and the beneficial effects of resveratrol on the amelioration of NAFLD in mice. We observed marked decreases in body weight and liver steatosis and improved insulin resistance in high-fat diet (HFD)-fed mice treated with resveratrol. Furthermore, we found that resveratrol treatment alleviated NAFLD in HFD-fed mice by improving the intestinal microenvironment, including gut barrier function and gut microbiota composition. On the one hand, resveratrol improved gut intestinal barrier integrity through the repair of intestinal mucosal morphology and increased the expression of physical barrier- and physiochemical barrier-related factors in HFD-fed mice. On the other hand, in HFD-fed mice, resveratrol supplementation modulated the gut bacterial composition. The resveratrol-induced gut microbiota was characterized by a decreased abundance of harmful bacteria, including Desulfovibrio, Lachnospiraceae_NK4A316_group and Alistipes, as well as an increased abundance of short-chain fatty acid (SCFA)-producing bacteria, such as Allobaculum, Bacteroides and Blautia. Moreover, transplantation of the HFDR-microbiota into HFD-fed mice sufficiently decreased body weight, liver steatosis and low-grade inflammation and improved hepatic lipid metabolism. Collectively, resveratrol would provide a potentially dietary intervention strategy against NAFLD through modulating the intestinal microenvironment.     

The relationship between oxidative stress and nonalcoholic fatty liver disease: Its effects on the development of nonalcoholic steatohepatitis

Abstract

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the most common underlying causes of chronic liver injury. They are associated with a wide spectrum of hepatic disorders including basic steatosis, steatohepatitis, and cirrhosis. The molecular and cellular mechanisms underlying hepatic injury in NAFLD and NASH are still unknown. This review describes the roles of oxidative stress and inflammatory responses in the pathogenesis of NAFLD and its progression to NASH.     

Fatty liver: Role of inflammation and fatty acid nutrition

Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver damage, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis. NAFLD is strongly associated with insulin resistance and is defined by accumulation of liver fat >5% per liver weight in the presence of <10 g of daily alcohol consumption. The exact prevalence of NAFLD is uncertain because of the absence of simple noninvasive diagnostic tests to facilitate an estimate of prevalence but in subgroups of people such as those with type 2 diabetes, the prevalence may be as high as 70%. NASH is an important subgroup within the spectrum of NAFLD that progresses over time with worsening fibrosis and cirrhosis, and NASH is associated with increased risk for cardiovascular disease. It is, therefore, important to understand the pathogenesis of NASH specifically, to develop strategies for interventions to treat this condition. The purpose of this review is to discuss the roles of inflammation, fatty acids and fatty acids in nutrition, in the pathogenesis and potential treatment of NAFLD.     

Amelioration of non-alcoholic steatohepatitis by Qushi Huayu decoction is associated with inhibition of the intestinal mitogen-activated protein kinase pathway

BackgroundGut microbiota is increasingly recognized as the key participant in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) by translocation of its products, such as lipopolysaccharide (LPS), via the dysfunctional intestinal barrier. Qushi Huayu decoction (QHD), a traditional Chinese medicine, is developed specially for NAFLD and used in clinic in China for more than a decade and previously found to ameliorate non-alcoholic steatohepatitis (NASH) induced by high-fat diet (HFD) in mice accompanied with inhibited metabolic endotoxemia and hepatic LPS signalling.PurposeTo investigate the mechanism of LPS gut-leakage inhibition by QHD in NASH.MethodsEffects of QHD on gut microbioa and intestinal barrier were evaluated in NASH induced by HFD in mice. 16S rRNA sequencing is employed to analyse the gut microbiota composition. To identify the potential signalling pathway responsible for tight junction regulation, the colonic phosphoprotein profile is screened via the Phospho Explorer Antibody Array and verified in NASH, intestinal barrier dysfunctional mouse and Caco-2 cells.ResultsQHD ameliorates NASH accompanied with regulating the gut microbiota composition, protecting intestinal tight junctions and inhibiting LPS gut-leakage without decreasing the abundance of identified Gram-negative bacteria. The validated data of phosphorylated proteins suggested that mitogen-activated protein kinase (MAPK) pathway is predominantly responsible for the colonic tight junction regulation by QHD.ConclusionQHD inhibits LPS gut-leakage in NASH, which is associated with downregulation of intestinal MAPK pathway.     

Expression of genes encoding mitochondrial proteins can distinguish nonalcoholic steatosis from steatohepatitis

In patients without substantial alcohol use, triglyceride accumulation in the liver can lead to nonalcoholic fatty liver disease (NAFLD) that may progress to nonalcoholic steatohepatitis (NASH). The differential diagnosis between NAFLD and NASH can be accomplished only by morphological examination. Although the relationship between mitochondrial dysfunction and the progression of liver pathologic changes has been described, the exact mechanisms initiating primary liver steatosis and its progression to NASH are unknown. We selected 16 genes encoding mitochondrial proteins which expression was compared by quantitative RT-PCR in liver tissue samples taken from patients with NAFLD and NASH. We found that 6 of the 16 examined genes were differentially expressed in NAFLD versus NASH patients. The expression of hepatic HK1, UCP2, ME2, and ME3 appeared to be higher in NASH than in NAFLD patients, whereas HMGCS2 and hnRNPK expression was lower in NASH patients. Although the severity of liver morphological injury in the spectrum of NAFLD-NASH may be defined at the molecular level, expression of these selected 6 genes cannot be used as a molecular marker aiding histological examination. Moreover, it is still unclear whether these differences in hepatic gene expression profiles truly reflect the progression of morphological abnormalities or rather indicate various metabolic and hormonal states in patients with different degrees of fatty liver disease.     

非酒精性脂肪性肝病的药物治疗进展

非酒精性脂肪性肝病已日渐成为目前慢性肝病的主要病因,其与肥胖、2型糖尿病和代谢综合征等疾病密切相关,疾病谱主要包括非酒精性单纯性脂肪肝、非酒精性脂肪性肝炎和肝硬化。早期诊断和及时治疗可望减轻NAFLD患者肝炎的严重程度并延缓肝纤维化的进展,减少并发症的出现。目前认为其发病与胰岛素抵抗、氧化应激及脂质过氧化和肠道菌群失调等因素有关。通过饮食调整和适当运动而减轻体重被认为是最基础的治疗措施,但单纯依靠减肥治疗脂肪性肝病(FLD)的效果并不理想,药物在脂肪性肝炎防治中的作用同样不可忽视。目前没有根治这一疾病的特效药物,单纯针对某一发病机制的药物亦难以治愈NAFLD这种复杂的疾病,本文主要从改善胰岛素抵抗、降脂、保肝抗炎及改善肠道菌群等四方面介绍一下本病的药物治疗进展。提倡改变生活方式的非药物治疗与药物干预治疗紧密结合,以取得最理想的治疗效果。     

Obesity-dependent metabolic signatures associated with nonalcoholic fatty liver disease progression

Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n=90) or diagnosed with NAFLD (steatosis, n=246; NASH, n=131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual's level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values=0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention.