白细胞介素-6在酒精性肝病中的作用

酒精性肝病(alcoholic liver disease,ALD)是由于长期过量饮酒导致肝的内部组织发生炎症损伤的慢性肝病.乙醇及其衍生物在代谢过程中直接或间接诱导引起的肝炎症反应可能是ALD发病的重要机制.然而,该过程内在的细胞分子机制尚不明确.最新研究发现,白细胞介素-6(interleukin-6,IL-6)对...     

Glycemic Variability Is an Independent Predictive Factor for Development of Hepatic Fibrosis in Nonalcoholic Fatty Liver Disease

Patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) often have metabolic disorders including insulin resistance and type 2 diabetes mellitus (T2DM). We clarified the predictive factors in glucose metabolism for progression of hepatic fibrosis in patients with NAFLD by the 75-g oral glucose tolerance test (75gOGTT) and a continuous glucose monitoring system (CGMS). One hundred sixty-nine patients (68 female and 101 male patients) with biopsy-proven NAFLD with performance with 75gOGTT were enrolled and divided into four groups according to the stage of hepatic fibrosis (F0–3). The proportion of patients with T2DM significantly gradually increased, HbA1c and the homeostasis model assessment of insulin resistance were significantly elevated, and 1,5-anhydroglucitol (1,5-AG) was remarkably decreased with the progression of fibrosis. In the 75gOGTT, both plasma glucose and insulin secretion were remarkably increased with the progression of fibrosis. The only factor significantly associated with advanced fibrosis was 1,5-AG (P = 0.008) as determined by multivariate logistic regression analysis. We next evaluated the changes in blood glucose during 24 hours by monitoring with the CGMS to confirm the relationship between glycemic variability and progression of fibrosis. Variability of median glucose, standard deviation of median glucose (P = 0.0022), maximum blood glucose (P = 0.0019), and ΔMin–max blood glucose (P = 0.0029) were remarkably higher in severe fibrosis than in mild fibrosis.

Conclusion

Hyperinsulinemia and hyperglycemia, especially glycemic variability, are important predictive factors in glucose impairment for the progression of hepatic fibrosis in NAFLD.     

肝细胞中活化转录因子ATF6抑制SREBP1的转录活性

内质网膜定位的活化转录因子ATF6和SREBP1均是经过蛋白酶切水解激活,激活后的ATF6(N)和SREBP1(N)进入细胞核内,分别指导内质网膜未折叠蛋白聚集反应相关基因和脂肪酸合成相关基因的表达.研究发现,肝细胞内葡萄糖饥饿激活ATF6并抑制SREBP1的转录活性及其靶基因的表达.过表达ATF6(N)能够抑制SREBP1介导的转录及其下游基因的表达.免疫共沉淀实验显示,ATF6(N)在细胞核内结合SREBP1(N),这种结合在无糖状况下增强.不同功能区缺失分析表明,ATF6和SREBP1通过亮氨酸拉链(leucinezipper)功能区相互作用.在葡萄糖饥饿状况下,ATF6对SREBP1转录活性的抑制保证了细胞基本生命活动所需要的能量.     

Direct Proteolytic Cleavage of NLRP1B Is Necessary and Sufficient for Inflammasome Activation by Anthrax Lethal Factor

Inflammasomes are multimeric protein complexes that respond to infection by recruitment and activation of the Caspase-1 (CASP1) protease. Activated CASP1 initiates immune defense by processing inflammatory cytokines and by causing a rapid and lytic cell death called pyroptosis. Inflammasome formation is orchestrated by members of the nucleotide-binding domain and leucine-rich repeat (NLR) or AIM2-like receptor (ALR) protein families. Certain NLRs and ALRs have been shown to function as direct receptors for specific microbial ligands, such as flagellin or DNA, but the molecular mechanism responsible for activation of most NLRs is still poorly understood. Here we determine the mechanism of activation of the NLRP1B inflammasome in mice. NLRP1B, and its ortholog in rats, is activated by the lethal factor (LF) protease that is a key virulence factor secreted by Bacillus anthracis, the causative agent of anthrax. LF was recently shown to cleave mouse and rat NLRP1 directly. However, it is unclear if cleavage is sufficient for NLRP1 activation. Indeed, other LF-induced cellular events have been suggested to play a role in NLRP1B activation. Surprisingly, we show that direct cleavage of NLRP1B is sufficient to induce inflammasome activation in the absence of LF. Our results therefore rule out the need for other LF-dependent cellular effects in activation of NLRP1B. We therefore propose that NLRP1 functions primarily as a sensor of protease activity and thus could conceivably detect a broader spectrum of pathogens than just B. anthracis. By adding proteolytic cleavage to the previously established ligand-receptor mechanism of NLR activation, our results illustrate the remarkable flexibility with which the NLR architecture can be deployed for the purpose of pathogen-detection and host defense.     

转录激活因子6：潜在的抗2 型糖尿病药物新靶点

真核细胞中的内质网是蛋白质合成、翻译和转运的场所,当内质网稳态被打破,出现蛋白质折叠障碍或错误折叠,并导致蛋白质过度积累时,便会引发内质网应激反应,即未折叠蛋白反应。大量的研究表明,内质网应激与2 型糖尿病的病理特征有一定的关系,而转录激活因子6 通路作为未折叠蛋白反应中3 条信号通路之一,调控着蛋白质的重折叠过程,对缓解内质网应激以及在糖脂代谢和胰岛素敏感性方面起着重要作用。简介内质网应激反应及相关信号通路和转录激活因子6,着重综述转录激活因子6 在肝脏糖脂代谢和胰岛素抵抗中的作用及相应机制,探讨其成为抗2 型糖尿病药物新靶点的可能性,为抗2 型糖尿病药物的研发提供新思路。     

Non-Alcoholic Fatty Liver Disease Is a Risk Factor for the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes Mellitus

Background

Non-alcoholic fatty liver disease (NAFLD) is prevalent in individuals with type 2 diabetes mellitus (T2DM). Diabetic nephropathy (DN) is also associated with T2DM. However, little is known about the interaction between these conditions in patients with T2DM.

Objective

To examine the association between NAFLD and DN in patients with T2DM.

Methods

This retrospective study included patients seen between January 2006 and July 2014.T2DM patients were divided into two groups based on NAFLD status (with NAFLD = group A; without = group B). The cumulative incidence of DN and chronic kidney disease (CKD) staging were compared between the two groups. Liver fat content was examined in some patients. Associations among NAFLD, other factors,and DN were analyzed by the additive interaction method.

Results

Cumulative incidence of DN in patients from group A (58.58%) was higher than in group B (37.22%) (P = 0.005). In both groups, the number of DN patients with CKD stage 1 was greater than the number of patients with stages 2–5. Increased liver fat content was associated with increased occurrence of severe and mild albuminuria and decreased glomerular filtration rate (GFR). There were positive correlations between NAFLD and insulin resistance index (HOMA-IR), free fatty acids (FFA), tumor necrosis factor-α (TNF-α), omentin-1, visceral fat area, homocysteine (HCY), and serum uric acid (UA).

Conclusion

NAFLD might be a risk factor for DN. Elevated liver fat content could be associated with higher DN burden.     

Alpha2 Macroglobulin-Like Is Essential for Liver Development in Zebrafish

Background

Alpha 2 Macroglobulin family members have been studied extensively with respect to their roles in physiology and human disease including innate immunity and Alzheimer''s disease, but little is known about a possible role in liver development loss-of-function in model systems.

Principal Findings

We report the isolation of the zebrafish α2 macroglobulin-like (A2ML) gene and its specific expression in the liver during differentiation. Morpholino-based knock-down of A2ML did not block the initial formation of the liver primordium, but inhibited liver growth and differentiation.

Significance

This report on A2ML function in zebrafish development provides the first evidence for a specific role of an A2M family gene in liver formation during early embryogenesis in a vertebrate.     

Obstructive Sleep Apnea Is Associated with Liver Damage and Atherosclerosis in Patients with Non-Alcoholic Fatty Liver Disease

Background/Aims

We assessed whether obstructive sleep apnea (OSA) and nocturnal hypoxemia are associated with severity of liver fibrosis and carotid atherosclerosis in patients with biopsy-proven NAFLD and low prevalence of morbid obesity. Secondary aim was to explore the association of OSA and hypoxemia with NASH and severity of liver pathological changes.

Methods

Consecutive patients (n = 126) with chronically elevated ALT and NAFLD underwent STOP-BANG questionnaire to estimate OSA risk and ultrasonographic carotid assessment. In patients accepting to perform cardiorespiratory polygraphy (PG, n = 50), OSA was defined as an apnea/hypopnea index ≥5. A carotid atherosclerotic plaque was defined as a focal thickening >1.3 mm.

Results

Prevalence of high OSA risk was similar in patients refusing or accepting PG (76% vs 68%, p = 0.17). Among those accepting PG, overall OSA prevalence was significantly higher in patients with F2-F4 fibrosis compared to those without (72% vs 44%; p = 0.04). Significant fibrosis was independently associated with mean nocturnal oxygen saturation (SaO₂)<95% (OR 3.21, 95%C.I. 1.02–7.34; p = 0.04). Prevalence of OSA tended to be higher in patients with, than in those without, carotid plaques (64% vs 40%; p = 0.08). Carotid plaques were independently associated with %time at SaO2<90% >1 (OR 6.30, 95%C.I. 1.02–12.3; p = 0.01).

Conclusions

In NAFLD patients with chronically elevated ALT at low prevalence of morbid obesity, OSA was highly prevalent and indexes of SaO₂ resulted independently associated with severity of liver fibrosis and carotid atherosclerosis. These data suggest to consider sleep disordered breathing as a potential additional therapeutic target in severe NAFLD patients.     

内毒素和细胞因子在酒精性肝病中的作用

酒精性肝病发病机制比较复杂,其中内毒素、细胞因子导致的肝细胞凋亡发挥了关键作用.酒精致肠道粘膜通透性增加,引起高内毒素血症,内毒素作用于kupffer细胞产生过量细胞因子如肿瘤坏死因子a(TNF-a)等,TNF-a与肝细胞表面的相应受体结合,诱导肝细胞凋亡,引起肝细胞损害.     

SD大鼠酒精性脂肪肝模型的监测分析

目的：通过血清生化指标和病理学的监测分析来建立标准的SD大鼠酒精性脂肪肝动物模型。方法：选取40只SD大鼠,随机分为两组,模型组采用直接饮酒法,于第8、12和20周时检测大鼠血清生化指标：丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、甘油三酯（TG）,并于第8、12周时随机采集5只大鼠肝组织,20周时采集剩余所有大鼠肝组织并进行病理学分析。结果：模型组于第8、12和20周时体重增长量均低于对照组（P〈0．01）,血清ALT、AST均高于对照组（P〈0．01）,第8周和12周时TG高于对照组（P〈0．01）。病理学结果显示肝组织从8周至20周呈现出酒精性脂肪肝、重度酒精性脂肪肝伴肝炎和酒精性肝纤维化等演变过程。结论：直接饮酒法可成功地复制出酒精性脂肪肝动物模型,通过监测分析可了解酒精性脂肪肝病变的整个过程,为今后建立酒精性脂肪肝和肝纤维化动物模型提供了理论参考。     

肝杀菌肽与酒精性肝病相关的铁过剩

酒精性肝病是一种由于过量食用酒精而导致的肝损伤性疾病,该病往往伴发肝脏铁过剩而出现铁沉积,进而导致肝纤维化甚至肝硬化而威胁生命.最新研究发现,酒精性肝病造成的铁过剩是由于一种铁调节激素肝杀菌肽的浓度异常所致,乙醇代谢可以减少肝杀菌肽在肝内的表达,肝杀菌肽浓度降低可使血清铁升高而引发肝脏铁沉积,这项研究为预防和治疗酒精性肝病的相关并发症带来了希望.     

重要转录因子FoxO3a在斑马鱼性腺中的表达分析

FoxO蛋白作为Forkhead Box家族的重要一员,在动物的生长发育、细胞分化、代谢、免疫和凋亡等方面起重要作用,研究发现FoxO蛋白是哺乳动物卵泡发育的重要调节因子.通过检测雌雄斑马鱼性腺中foxo3a基因的表达情况,初步研究FoxO在鱼类生殖发育中的作用.PCR和蛋白免疫杂交结果都显示foxo3a基因在斑马鱼雌性性腺中的表达量要明显高于雄性.这一结果提示,foxo3a基因在斑马鱼的卵巢发育中可能发挥重要作用.