蓝莓对非酒精性脂肪性肝病小鼠肝细胞核因子相关因子2表达的影响

目的:研究蓝莓对非酒精性脂肪性肝病(NAFLD)小鼠的保护作用及相关机制。方法:40只健康C57BL/6J小鼠随机分为4组:正常组、蓝莓组、姜黄素组、模型组。正常组饲喂正常饲料,其余各组饲喂高脂饲料。蓝莓组每日灌胃蓝莓原浆(15 ml·kg-1·d-1);姜黄素组每日灌胃姜黄素溶液(200mg·kg-1·d-1);其余组小鼠灌胃等体积生理盐水,12周后处死。油红染色观察各组肝脏形态变化;全自动生化分析仪检测血清中丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、三酰甘油(TG)、总胆固醇(TC)含量;酶联免疫法检测肝组织中超氧化物歧化酶(SOD)活性、谷胱甘肽(GSH)、丙二醛(MDA)及三酰甘油(TG)含量;Western blot检测小鼠肝组织中核因子相关因子2(Nrf2)蛋白的表达。结果:与模型组小鼠相比,蓝莓组、姜黄素组油红染色肝组织中脂肪沉积明显减少,血清AST、ALT、TG、TC含量明显降低(P0.05),肝组织中TG、MDA含量明显下降(P0.05),而SOD活性、GSH含量及Nrf2蛋白表达明显增高(P0.05)。结论:蓝莓对NAFLD有较好的防治作用,其机制可能与上调肝组织中Nrf2的表达,提高机体抗氧化能力相关。     

脂肪因子在非酒精性脂肪性肝病中的作用

非酒精性脂肪性肝病(NAFLD)是一种慢性进行性肝病,其发病与肥胖、2型糖尿病密切相关。脂肪组织能产生和分泌具有促炎和抗炎特性的细胞因子,在NAFLD发病过程中起着至关重要的作用。脂联素和瘦素在NAFLD的病理生理学方面具有明确的作用,其他脂肪因子如抵抗素、内脂素、趋化素、视黄醇结合蛋白4、丝氨酸蛋白酶抑制剂、Apelin等在NAFLD发病机制和进展中的作用需要进一步研究。此外,用于治疗NAFLD的药物如噻唑烷二酮类、他汀类药物等对脂肪因子水平产生有利影响,可能有助于改善肝功能。该文对脂肪因子与NAFLD之间的关系作一综述,并讨论脂肪因子作为NAFLD潜在治疗靶点的意义。     

非酒精性脂肪性肝病相关肝细胞癌的研究进展

非酒精性脂肪性肝病相关肝细胞癌发病率在世界范围内呈增长趋势,然而其发病机制仍不明确。结合近年文献,总结脂肪组织炎症、氧化应激、肠道菌群及胰岛素抵抗在非酒精性脂肪性肝病相关肝细胞癌发病过程中的作用,并针对以上机制的防治进展进行综述,为其治疗提供新思路。     

从非酒精性脂肪性肝病到代谢相关脂肪性肝病的变迁

非酒精性脂肪性肝病(NAFLD)是全球范围最常见的慢性肝病,且进展至肝纤维化、肝硬化、肝癌等不良结局加重社会医疗负担。NAFLD特征是肝脏脂肪沉积和炎症,近40余年以来一直是一个排他性诊断,随着研究不断地深入,2020至2023年期间经历了两次更名,从代谢相关脂肪性肝病(MAFLD)到代谢功能障碍相关脂肪性肝病(MASLD)。本文讨论了目前对NAFLD/MAFLD/MASLD特征的对比、临床和研究问题,旨在提高我们对脂肪性肝病(SLD)的全面理解。     

脂肪细胞因子在非酒精性脂肪性肝病中的作用

非酒精性脂肪性肝病的发生与肥胖、脂质代谢异常和胰岛素抵抗密切相关.脂肪细胞具有内分泌功能,其分泌的瘦素、脂联素、肿瘤坏死因子、过氧化物酶体增殖物激活受体、抵抗素、白介素-6、白介素-8、内脏脂肪素、纤溶酶原激活抑制物-1等在非酒精性脂肪性肝病的发生发展中起重要作用.本文对其深入研究为临床治疗提供新的思路与方法.     

胆汁酸核受体和脂肪因子在非酒精性脂肪性肝病发病中的作用

非酒精性脂肪性肝病是世界范围内最常见的一种慢性肝病,胰岛素抵抗是其主要的发病原因之一,但其具体发病机制尚不十分明确。近年研究发现影响胆汁酸核受体的措施具有改善胰岛素抵抗和抗肝纤维化等作用。脂肪细胞分泌的多种脂肪因子在非酒精性脂肪性肝病的发生、发展中也起着重要的作用。另外,研究还发现胆汁酸核受体的变化可影响脂肪因子的分泌。     

内质网应激相关炎性反应及其在非酒精性脂肪性肝病中的作用

内质网是真核生物重要的细胞器,当内质网功能发生障碍时,可引起细胞发生内质网应激反应(ERS)。ERS经蛋白激酶样内质网激酶(PERK)、需肌醇酶-1α(IRE-1α)及活化转录因子-6α(ATF-6α)等多种信号通路介导发生炎性反应,参与非酒精性脂肪性肝病(NAFLD)胰岛素抵抗(IR)的形成及进展至非酒精性脂肪性肝炎(NASH)、纤维化等过程。通过调控ERS相关炎性反应可能为防治NAFLD提供一条新的途径。     

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。     

非酒精性脂肪性肝病相关肝癌的临床特征

非酒精性脂肪性肝病相关性肝癌(non-alcoholic fatty liver disease-hepatocellular carcinoma，NAFLD-HCC) 发病率逐渐升高，已成为肝癌的主要类型。因此，提高NAFLD-HCC 的临床诊治水平具有重要意义。该文对 NAFLD-HCC 的临床特征进行总结，发现其具有特殊的自然病程，同时具有起病隐匿、男性多见、常合并代谢综合 征、肿瘤单发且分化较好等特点。血清学、CT 影像学以及病理对NAFLD-HCC 诊断具有重要价值。改善生活习惯 和加强锻炼可预防NAFLD-HCC 发生，然而药物和手术治疗仍是最重要的治疗手段。NAFLD-HCC 治疗效果与 其他肝癌类型相比差异无统计学意义。不断总结临床特征将有助于提高NAFLD-HCC 诊治水平，同时需要不断探 索NAFLD-HCC 的发病机制，进而制定NAFLD-HCC 的个体化防治策略具有重要意义。     

Nuclear factor erythroid 2-related factor 2-mediated signaling and metabolic associated fatty liver disease

Oxidative stress is a key driver in the development and progression of several diseases, including metabolic associated fatty liver disease (MAFLD). This condition includes a wide spectrum of pathological injuries, extending from simple steatosis to inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Excessive buildup of lipids in the liver is strictly related to oxidative stress in MAFLD, progressing to liver fibrosis and cirrhosis. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of redox homeostasis. NRF2 plays an important role for cellular protection by inducing the expression of genes related to antioxidant, anti-inflammatory, and cytoprotective response. Consistent evidence demonstrates that NRF2 is involved in every step of MAFLD deve-lopment, from simple steatosis to inflammation, advanced fibrosis, and ini-tiation/progression of hepatocellular carcinoma. NRF2 activators regulate lipid metabolism and oxidative stress alleviating the fatty liver disease by inducing the expression of cytoprotective genes. Thus, modulating NRF2 activation is crucial not only in understanding specific mechanisms underlying MAFLD progression but also to characterize effective therapeutic strategies. This review outlined the current knowledge on the effects of NRF2 pathway, modulators, and mechanisms involved in the therapeutic implications of liver steatosis, inflammation, and fibrosis in MAFLD.     

Endocannabinoid receptor CB2 in nonalcoholic fatty liver disease.

BACKGROUND AND AIM: Fatty infiltration and fibrosis are major issues in chronic liver disease. Recent reports suggest a role for the endocannabinoid system in these processes. AIM: To characterize localization and expression of CB2 in normal liver and nonalcoholic fatty liver. METHODS: We studied 64 liver biopsies: eight were considered normal; 56 had a diagnosis of nonalcoholic fatty liver disease (NAFLD); 32 with nonalcoholic steatosis and 24 nonalcoholic steatohepatitis (NASH). CB2 immunolocalization was studied in 38 samples in paraffin blocks using immunohistochemistry, and a computerized semiquantitative analysis was carried out. CB2 mRNA expression was assessed through RT-PCR in 26 frozen liver samples and the ratio CB2/beta-actin was used to evaluate differences between groups. Statistical analysis was performed with central tendency measures and the Mann-Whitney U-test. We considered as significant differences those with a P-value <0.05. RESULTS: Neither parenchymal nor nonparenchymal cells in normal liver tissue react towards anti-CB2 antibodies. All the samples from patients with steatosis and nonalcoholic steatohepatitis showed hepatocellular immunoreactivity. Cholangiocytes were positive only in the NAFLD group. Normal liver tissue showed a normalized CB2/beta-actin ratio of 0.001+/-0.01, steatosis 6.52+/-17.3 (P=0.05 vs normal) and NASH 6.49+/-12.2 (P=0.06 vs normal and P=0.6 vs steatosis). CONCLUSION: CB2 receptors are expressed by hepatocytes in nonalcoholic fatty liver disease but not in normal liver.     

The role of bariatric surgery in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Introduction: Nonalcoholic fatty liver disease (NAFLD) affects between 25% and 33% of the population, is more common in obese individuals, and is the most common cause of chronic liver disease in the United States. However, despite rising prevalence, effective treatments remain limited.

Areas covered: We performed a literature search across multiple databases (Pubmed, Medline, etc.) to identify significant original research and review articles to provide an up-to-date and concise overview of disease pathogenesis and diagnostic evaluation and to expand on available treatment options with a specific focus on the potential role of bariatric surgery. Here we provide the most comprehensive review of bariatric surgery for the management of NAFLD, noting benefits from different procedures and multiple reports showing improvements in steatosis, inflammation and fibrosis over the duration of follow-up.

Expert commentary: The morbidity of NAFLD is significant as it may become the most common indication for liver transplantation within the next 5 years. In addition to known benefits of weight loss and diabetes resolution, bariatric surgery has the potential to halt and reverse disease progression and future controlled trials should be performed to further define its benefit in the treatment of NAFLD in morbidly obese patients.     

Interaction of Type 2 diabetes and nonalcoholic fatty liver disease

Evauation of: Kasturiratne A, Weerasinghe S, Dassanayake A et al. Influence of non-alcoholic fatty liver disease on the development of diabetes mellitus. J. Gastroenterol. Hepatol. 28(1), 142–147 (2013).

It has been a few decades that Type 2 diabetes has been clearly linked to the development and progression of nonalcoholic fatty liver disease (NAFLD). In a recent study reported by Kastuiratne et al., the reverse scenario is also reported. In this study, a cohort of Sri Lankan adults were evaluated for NAFLD by ultrasound and for the presence of Type 2 diabetes. Those without diabetes at baseline were followed prospectively for 3 years and assessed for incident diabetes. On multivariate analysis, after adjustment for a number of factors (age, impaired fasting glucose, BMI, waist circumference, elevated ALT, family history of diabetes and presence of hypertension and hyperlipidemia), NAFLD was the only predictor of incident diabetes in those with and without impaired fasting glucose at baseline. This study adds to the growing evidence connecting NAFLD to Type 2 diabetes and highlights the importance of its recognition in an effort to target those at the highest risk of diabetes for lifestyle and pharmacologic intervention.     

虎杖苷对非酒精性脂肪性肝病胰岛素抵抗及氧化应激影响的实验研究

[目的]研究虎杖苷治疗对非酒精性脂肪性肝病（NAFLD）胰岛素抵抗（IR）及氧化应激的影响。[方法]健康雄性SD大鼠47只,随机分为5组：正常组（10只）、模型组（10只）、虎杖苷大剂量组（9只）、虎杖苷小剂量组（9只）和双环醇组（9只）。正常组予标准饲料,其他4组给予高脂饲料造模;5组共喂养10周后,从正常组与模型组中各随机挑选1只大鼠,取肝脏做病理切片,证实大鼠NAFLD模型的形成。正常组与模型组予以0．9％氯化钠灌胃,5ml／次;虎杖苷大、小剂量组分别以200mg／（kg·d）、100mg／（kg·d）的虎杖苷混悬液灌胃;双环醇组以100mg／（kg·d）的双环醇混悬液灌胃。给药4周,期间各组大鼠统一用标准饲料饲养。次日大鼠禁食12h后,腹腔麻醉,抽取腹主动脉血5ml,分离血清,检测大鼠血清中氧化应激因子丙二醛（MDA）、总超氧化物歧化酶（T-SOD）、羟自由基（-OH）、谷胱甘肽一孓转移酶（GST）水平及血清总抗氧化能力（T-AOC）水平;试剂盒检测空腹血糖、胰岛素水平,计算IR指数（IRI）和胰岛素敏感指数;ELISA法检测大鼠血清肿瘤坏死因子-α（TNF-α）水平。[结果]高脂饮食饲养10周后,模型组大鼠血清-OH、MDA、TNF-α较正常组均显著增高（P〈0．05～〈0．01）,GST、T-SOD、T-AOC活性降低（P〈0．01）,与模型组相比,虎杖苷治疗后,-OH、MDA、TNF-α浓度降低（P〈0．05〈0．01）,而T-SOD及T-AOC的活性恢复（P〈0．05～〈0．01）,IR明显改善（P〈0．05～〈0．01）。[结论]IR和氧化应激关系密切,氧化应激是发生IR的重要原因之一,虎杖苷的抗氧化应激效应是改善IR的部分机制。     

Sampling variability of liver biopsy in nonalcoholic fatty liver disease

BACKGROUND & AIMS: In nonalcoholic fatty liver disease (NAFLD), the distinction between steatosis and steatohepatitis (NASH) and the assessment of the severity of the disease rely on liver histology alone. The aim of this study was to assess the sampling error of liver biopsy and its impact on the diagnosis and staging of NASH. METHODS: Fifty-one patients with NAFLD underwent percutaneous liver biopsy with 2 samples collected. The agreement between paired biopsy specimens was assessed by the percentage of discordant results and by the kappa reliability test. RESULTS: No features displayed high agreement; substantial agreement was only seen for steatosis grade; moderate agreement for hepatocyte ballooning and perisinusoidal fibrosis; fair agreement for Mallory bodies; acidophilic bodies and lobular inflammation displayed only slight agreement. Overall, the discordance rate for the presence of hepatocyte ballooning was 18%, and ballooning would have been missed in 24% of patients had only 1 biopsy been performed. The negative predictive value of a single biopsy for the diagnosis of NASH was at best 0.74. Discordance of 1 stage or more was 41%. Six of 17 patients with bridging fibrosis (35%) on 1 sample had only mild or no fibrosis on the other and therefore could have been under staged with only 1 biopsy. Intraobserver variability was systematically lower than sampling variability and therefore could not account for most of the sampling error. CONCLUSIONS: Histologic lesions of NASH are unevenly distributed throughout the liver parenchyma; therefore, sampling error of liver biopsy can result in substantial misdiagnosis and staging inaccuracies.     

Crosstalk between nonalcoholic fatty liver disease and cardiometabolic syndrome

Nonalcoholic fatty liver disease (NAFLD) is a chronic condition characterized by fat accumulation combined with low‐grade inflammation in the liver. A large body of clinical and experimental data shows that increased flux of free fatty acids from increased visceral adipose tissue and de novo lipogenesis can lead to NAFLD and insulin resistance. Thus, individuals with obesity, insulin resistance, and dyslipidaemia are at the greatest risk of developing NAFLD. Conversely, NAFLD is a phenotype of cardiometabolic syndrome. Notably, researchers have discovered a close association between NAFLD and impaired glucose metabolism and focused on the role of NAFLD in the development of type 2 diabetes. Moreover, recent studies provide substantial evidence for an association between NAFLD and atherosclerosis and cardiometabolic disorders. Even if NAFLD can progress into severe liver disorders including nonalcoholic steatohepatitis (NASH) and cirrhosis, the majority of subjects with NAFLD die from cardiovascular disease eventually. In this review, we propose a potential pathological link between NAFLD/NASH and cardiometabolic syndrome. The potential factors that can play a pivotal role in this link, such as inflammation, insulin resistance, alteration in lipid metabolism, oxidative stress, genetic predisposition, and gut microbiota are discussed.     

2型糖尿病和非酒精性脂肪肝与脂肪细胞因子的相关性

目的研究2型糖尿病和非酒精性脂肪肝（NAFLD）与脂肪细胞因子的相关性。方法240例受试者分为正常对照组47例（A组）、非酒精性脂肪肝组53例（B组）、2型糖尿病组79例（C组）、2型糖尿病伴非酒精性脂肪肝组61例（D组）,进行肝功、血脂、血糖、胰岛素水平、血尿酸、脂联素（APN）、肿瘤坏死因子（TNF-d）的测定以及腹部B超检查。结果B组体质量、体质量指数、腰围、血脂、胰岛素水平、胰岛素抵抗指数（HOMA．IR）、肝酶、血尿酸显著高于A组（P〈0．01）;B细胞功能评估显著低于A组（P〈0．01）;其空腹胰岛素水平、胆固醇、甘油三酯、血尿酸水平、丙氨酸转氨酶（ALT）、y-谷氨酰转移酶（GGT）高于C组（P〈0．01）。D组体质量、腰围、空腹胰岛素水平、甘油三酯、HOMA．IR、ALT、GGT显著高于C组（P〈0．01）,其血压、HOMA．IR显著高于B组（P〈0．01）。B组,C组,D组与A组相比APN明显下降（P〈0．01）,TNF-a明显升高（P〈0．01）,D组与B组,C组相比ANP下降（P〈0．01）,TNF-a上升（P〈0．01）。Logistic回归分析发现,甘油三酯、TNF．d为NAFLD的独立危险因素。Spearman相关分析显示,ANP与HOMA．IR、甘油三酯、腰围、TNF-a呈负相关,TNF-a与空腹胰岛素及HOMA．IR呈正相关,与ANP呈负相关。结论脂肪细胞因子参与2型糖尿病、NAFLD病理生理过程,恢复脂肪细胞因子的水平是非常有意义的。