代谢性炎症与非酒精性脂肪性肝病的发生与发展

代谢性炎症在非酒精性脂肪性肝病(NAFLD)的发生与发展过程中扮演了极其重要的角色。现重点论述肝脏炎症的产生,以及炎症应激下肝细胞内脂质稳态失衡、脂质发生"二次异常转运",过多的脂质又通过内质网应激、氧化应激等发挥脂毒性作用,加重和放大肝脏的炎症效应,从而导致NAFLD由单纯性肝脂肪变性向脂肪性肝炎演变的病理生理过程,旨在为临床深入了解NAFLD的发病机制和发现新的治疗靶点提供理论依据。     

脂毒性在非酒精性脂肪性肝炎中的作用机制

非酒精性脂肪性肝炎(NASH)作为非酒精性脂肪性肝病(NAFLD)病情加剧的重要环节,炎症和肝损伤是该阶段的重要病理学特征。脂毒性作为NASH的致病机制之一,能够通过多种途径调控肝脏的炎症和肝细胞凋亡。本文从炎症和肝细胞凋亡两个层面重点阐述脂毒性对NASH的具体调控机制,其中涉及了多种肝脏非实质细胞和JNK、NF-κB、caspase介导的细胞凋亡等信号通路,为临床NASH的诊断和治疗提供了新思路。     

AMPK激活在非酒精性脂肪性肝病中的研究进展

非酒精性脂肪性肝病(NAFLD)的发生和进展与脂质积累、胰岛素抵抗、炎症、肝损伤、纤维化等因素有关。AMP依赖蛋白激酶(AMPK)是调控生物能量代谢的关键分子, 参与调控脂质代谢、自噬、炎症和细胞凋亡等众多生物过程。促进AMPK激活可减轻肝脏脂质积累和胰岛素抵抗, 缓解NAFLD的发展, 减轻肝脏炎症和纤维化抑制NAFLD向非酒精性脂肪性肝炎进展。     

肝脏免疫炎症在非酒精性脂肪性肝病发生发展中的作用

非酒精性脂肪性肝病(NAFLD)是临床上常见的肝脏疾病之一,其发病机制较为复杂,"二、三次打击"学说仍是目前得到公认的NAFLD的主要发病机制。但近年来,肝脏免疫炎症在NAFLD的发生、发展中逐步得到众多研究者的重视。从肝脏免疫炎症的角度,阐述了肝脏免疫炎症导致NAFLD发生、发展的机制。     

环氧合酶-2与非酒精性脂肪性肝炎关系的研究进展

非酒精性脂肪性肝炎( NASH)呈慢性肝脏脂毒性炎症表现,是非酒精性脂肪性肝病(NAFLD)的重要转折点,存在肝病重症化趋势.环氧合酶-2(COX -2)作为启动炎症反应的关键酶同样涉及到NASH的形成及进展.本文就COX -2及其抑制剂与NASH关系的研究予以综述.     

噻唑烷二酮类对NASH的作用——系统回顾和荟萃分析

非酒精性脂肪性肝病(NAFLD)被认为是代谢综合征在肝脏的一个表现,普遍认为和胰岛素抵抗(IR)有关,当存在二次(或多次)打击,包括氧化应激、内质网应激、游离脂肪酸的脂毒性、细胞因子和肠道菌群失调等,就会导致细胞脂肪变性、炎症坏死和疾病的进展(综合反应假说),即处于非酒精性脂肪性肝炎(NASH)状态.     

高脂饮食对实验性大鼠非酒精性脂肪肝UCP2表达的影响

目的:通过高脂饮食制作非酒精性脂肪肝(NAFLD)动物模型;观察高脂饮食对实验性大鼠NAFLD解偶联蛋白2(UCP2)的影响。方法:通过高脂饮食建立大鼠非酒精性脂肪性肝病模型。观察肝脏病理改变并检测肝脏UCP2表达情况。结果:与正常对照组相比,高脂饮食大鼠肝脏UCP2表达显著上升,肝组织广泛脂肪变性,形成单纯性脂肪肝。继续给予高脂饮食使肝脏UCP2表达水平进一步增加,肝脏发生进一步病理改变而形成脂肪性肝炎。结论:高脂饮食成功地复制了NAFLD动物模型;NAFLD时肝脏UCP2表达上调,可能是机体的一种适应性反应;但是UCP2过度表达,可能诱导或加剧肝脏病理改变。     

非酒精性脂肪性肝炎的发病机制: 病理生理学和分子生物学

非酒精性脂肪性肝炎以肝脏脂肪浸润、炎症、肝细胞损害和纤维化为特征, 可进一步发展为肝硬化及肝癌. 游离脂肪酸向肝内转运和肝脏脂肪酸的从头合成导致肝细胞内脂肪超负载. 脂毒性引起氧化应激、炎症反应和肝细胞凋亡. 随后慢性肝损伤激活纤维化反应发展至终末期肝病. 对非酒精性脂肪性肝炎病理生理学和分子生物学发病机制的深入研究将有利于临床诊断和治疗.     

非酒精性脂肪肝研究新进展

非酒精性脂肪性肝病（NAFLD）是代谢综合征表现为一组肝脏病变的总称，包括2型糖尿病（T2DM）、胰岛素耐受、脂质代谢障碍和高血压。NAFLD的特点是大囊泡状脂肪变性，范围从单一的脂肪肝到非酒精性脂肪性肝炎（NASH）；随后由单纯的脂肪变性向炎症／纤维化疾病发展。持续性的肝脏损伤将导致肝脏向纤维化或肝硬化发展。[第一段]     

肥胖症与非酒精性脂肪性肝病的关系及其治疗进展

非酒精性脂肪性肝病（NAFLD）是一种除外酒精和其他明确肝损因素的慢性肝脏疾病，其发病与肥胖、胰岛素抵抗等密切相关。肿瘤坏死因子（TNF）-α、脂联素等脂肪因子在NAFLD的发生、发展中起重要作用。在肝细胞脂肪变性的基础上发生氧化应激，引起炎症损伤的“二次打击”学说，是目前广泛认可的对NAFLD发病机制的解释。对肥胖患者行饮食、运动、行为、药物、手术治疗等可改善肥胖相关慢性炎症环境，是防治NAFLD重要而有效的手段。     

Lipidomics in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disorder in Western countries, comprises steatosis to nonalcoholic steatohepatitis (NASH), with the latter having the potential to progress to cirrhosis. The transition from isolated steatosis to NASH is still poorly understood, but lipidomics approach revealed that the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis and these alterations correlate with disease progression. Recent data suggest that both quantity and quality of the accumulated lipids are involved in pathogenesis of NAFLD. Changes in glycerophospholipid, sphingolipid, and fatty acid composition have been described in both liver biopsies and plasma of patients with NAFLD, implicating that specific lipid species are involved in oxidative stress, inflammation, and cell death. In this article, we summarize the findings of main human lipidomics studies in NAFLD and delineate the currently available information on the pathogenetic role of each lipid class in lipotoxicity and disease progression.     

Body weight loss and glycemic control on the outcomes of patients with NAFLD. The role of new antidiabetic agents

Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide affecting a third of adults and 12% of children in Western countries. In around 50–60%% of cases, NAFLD and type 2 diabetes mellitus (T2DM) coexist and act synergistically to increase the risk of adverse hepatic and extra-hepatic outcomes. T2DM is a strong risk factor for rapid progression of NAFLD to nonalcoholic steatohepatitis (NASH), cirrhosis or hepatocellular carcinoma (HCC), which have become frequent indications of liver transplantation.The pathophysiology of NAFLD is complex and its relationship with T2DM is bidirectional, where lipotoxicity and insulin resistance (IR), act as the strongest pillars.To date, no pharmacological treatment has been approved for NAFLD. However, there is an intense research with numerous drugs focused on reversing inflammation and liver fibrosis through modulation of molecular targets without good results.It has been known for some time that weight reduction >10% is associated to histological improvement of NAFLD. Recently, glycemic control has been shown to induce similar results. Diet and physical exercise for weight reduction have limitations, so alternative methods (pharmacologic, endoscopic or surgical) may be required. Currently, new antidiabetic drugs inducing weight loss, have been recently approved for the treatment of obesity. Nevertheless, their therapeutic effects on NAFLD have not been extensively studied.We will review here, recently published data on the effects of weight loss and glycemic control on the histological and metabolic parameters of NAFLD and recent published data on therapeutic studies of NAFLD with new antidiabetic drugs.     

Prevention of free fatty acid-induced hepatic lipotoxicity by 18beta-glycyrrhetinic acid through lysosomal and mitochondrial pathways

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and affects millions of people worldwide. Despite the increasing prevalence of NAFLD, the exact molecular/cellular mechanisms remain obscure and effective therapeutic strategies are still limited. It is well-accepted that free fatty acid (FFA)-induced lipotoxicity plays a pivotal role in the pathogenesis of NAFLD. Inhibition of FFA-associated hepatic toxicity represents a potential therapeutic strategy. Glycyrrhizin (GL), the major bioactive component of licorice root extract, has a variety of pharmacological properties including anti-inflammatory, antioxidant, and immune-modulating activities. GL has been used to treat hepatitis to reduce liver inflammation and hepatic injury; however, the mechanism underlying the antihepatic injury property of GL is still poorly understood. In this report, we provide evidence that 18 beta-glycyrrhetinic acid (GA), the biologically active metabolite of GL, prevented FFA-induced lipid accumulation and cell apoptosis in in vitro HepG2 (human liver cell line) NAFLD models. GA also prevented high fat diet (HFD)-induced hepatic lipotoxicity and liver injury in in vivo rat NAFLD models. GA was found to stabilize lysosomal membranes, inhibit cathepsin B expression and enzyme activity, inhibit mitochondrial cytochrome c release, and reduce FFA-induced oxidative stress. These characteristics may represent major cellular mechanisms, which account for its protective effects on FFA/HFD-induced hepatic lipotoxicity. CONCLUSION: GA significantly reduced FFA/HFD-induced hepatic lipotoxicity by stabilizing the integrity of lysosomes and mitochondria and inhibiting cathepsin B expression and enzyme activity.     

Complicaciones extrahepáticas de la enfermedad por hígado graso no alcohólico: impacto más allá del hígado

Non-alcoholic fatty liver disease (NAFLD) is currently one of the main causes of chronic liver disease in Western countries, with a 25% prevalence reported in the general population worldwide. Visceral adiposity and liver fat promote a state of systemic inflammation, predisposing individuals with NAFLD to the extrahepatic pathologies of cardiovascular disease (the most common cause of death in patients with NAFLD), diabetes mellitus, chronic kidney disease, hypothyroidism, polycystic ovary syndrome, obstructive sleep apnea, and an increased risk for presenting with gastrointestinal and extraintestinal neoplasias. Different mechanisms between NAFLD and its association with extrahepatic diseases have been reported, and lipotoxicity is the main cause of inflammatory pathway activation that results in extrahepatic tissue damage.     

NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications

While non-alcoholic fatty liver disease (NAFLD) is highly prevalent (15% to 45%) in modern societies, only 10% to 25% of cases develop hepatic fibrosis leading to cirrhosis, end-stage liver disease or hepatocellular carcinoma. Apart from pre-existing fibrosis, the strongest predictor of fibrotic progression in NAFLD is steatohepatitis or non-alcoholic steatohepatitis (NASH). The critical features other than steatosis are hepatocellular degeneration (ballooning, Mallory hyaline) and mixed inflammatory cell infiltration. While much is understood about the relationship of steatosis to metabolic factors (over-nutrition, insulin resistance, hyperglycemia, metabolic syndrome, hypoadiponectinemia), less is known about inflammatory recruitment, despite its importance for the perpetuation of liver injury and fibrogenesis. In this review, we present evidence that liver inflammation has prognostic significance in NAFLD. We then consider the origins and components of liver inflammation in NASH. Hepatocytes injured by toxic lipid molecules (lipotoxicity) play a central role in the recruitment of innate immunity involving Toll-like receptors (TLRs), Kupffer cells (KCs), lymphocytes and neutrophils and possibly inflammasome. The key pro-inflammatory signaling pathways in NASH are nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK). The downstream effectors include adhesion molecules, chemokines, cytokines and the activation of cell death pathways leading to apoptosis. The upstream activators of NF-κB and JNK are more contentious and may depend on the experimental model used. TLRs are strong contenders. It remains possible that inflammation in NASH originates outside the liver and in the gut microbiota that prime KC/TLR responses, inflamed adipose tissue and circulating inflammatory cells. We briefly review these mechanistic considerations and project their implications for the effective treatment of NASH.     

G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment

Nonalcoholic fatty liver disease(NAFLD)is a broad-spectrum disease,ranging from simple hepatic steatosis to nonalcoholic steatohepatitis,which can progress to cirrhosis and liver cancer.Abnormal hepatic lipid accumulation is the major manifestation of this disease,and lipotoxicity promotes NAFLD progression.In addition,intermediate metabolites such as succinate can stimulate the activation of hepatic stellate cells to produce extracellular matrix proteins,resulting in progression of NAFLD to fibrosis and even cirrhosis.G protein-coupled receptors(GPCRs)have been shown to play essential roles in metabolic disorders,such as NAFLD and obesity,through their function as receptors for bile acids and free fatty acids.In addition,GPCRs link gut microbiota-mediated connections in a variety of diseases,such as intestinal diseases,hepatic steatosis,diabetes,and cardiovascular diseases.The latest findings show that gut microbiota-derived acetate contributes to liver lipogenesis by converting dietary fructose into hepatic acetyl-CoA and fatty acids.GPCR agonists,including peptides and natural products like docosahexaenoic acid,have been applied to investigate their role in liver diseases.Therapies such as probiotics and GPCR agonists may be applied to modulate GPCR function to ameliorate liver metabolism syndrome.This review summarizes the current findings regarding the role of GPCRs in the development and progression of NAFLD and describes some preclinical and clinical studies of GPCR-mediated treatment.Overall,understanding GPCR-mediated signaling in liver disease may provide new therapeutic options for NAFLD.     

Liver fat as risk factor of hepatic and cardiometabolic diseases

Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by excessive accumulation of fat in the liver that can progress to liver inflammation (non-alcoholic steatohepatitis [NASH]), liver fibrosis, and cirrhosis. Although most efforts for drug development are focusing on the treatment of the latest stages of NAFLD, where significant fibrosis and NASH are present, findings from studies suggest that the amount of liver fat may be an important independent risk factor and/or predictor of development and progression of NAFLD and metabolic diseases. In this review, we first describe the current tools available for quantification of liver fat in humans and then present the clinical and pathophysiological evidence that link liver fat with NAFLD progression as well as with cardiometabolic diseases. Finally, we discuss current pharmacological and non-pharmacological approaches to reduce liver fat and present open questions that have to be addressed in future studies.     

内质网应激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(NAFLD)的发病率在全球范围内迅速增加,但其发病的确切机制并不十分清楚。一方面探讨内质网应激(ERS)可以通过未折叠氮蛋白反应(URP)促进NAFLD的形成及进展为非酒精性脂肪性肝炎(NASH),另一方面探讨NAFLD的脂质环境,尤其是脂肪酸,又可诱发ERS的发生。从而指出ERS相关信号转导在NAFLD发病机制中的作用,为NAFLD的治疗提供新的思路。     

Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway

Nonalcoholic fatty liver disease (NAFLD) is a serious health problem. Although NAFLD represents a form of lipotoxicity, its pathogenesis remains poorly understood. The aim of this study was to examine the cellular mechanisms involved in free fatty acid (FFA)-mediated hepatic lipotoxicity. FFA treatment of liver cells resulted in Bax translocation to lysosomes and lysosomal destabilization with release of cathepsin B (ctsb), a lysosomal cysteine protease, into the cytosol. This process was also partially dependent on ctsb. Lysosomal destabilization resulted in nuclear factor kappa B-dependent tumor necrosis factor alpha expression. Release of ctsb into the cytoplasm was also observed in humans with NAFLD and correlated with disease severity. In a dietary murine model of NAFLD, either genetic or pharmacological inactivation of ctsb protected against development of hepatic steatosis, liver injury, and insulin resistance with its associated "dysmetabolic syndrome." In conclusion, these data support a lipotoxic model of FFA-mediated lysosomal destabilization.