Endoplasmic reticulum stress is involved in hepatic SREBP-1c activation and lipid accumulation in fructose-fed mice

A link between fructose drinking and nonalcoholic fatty liver disease (NAFLD) has been demonstrated in human and rodent animals. The aim of the present study was to investigate whether endoplasmic reticulum (ER) stress is mediated in the development of fructose-induced NAFLD. Female CD-1 mice were fed with 30% fructose solution for eight weeks. Hepatic lipid accumulation was assessed. Hepatic nuclear sterol regulatory element-binding protein (SREBP)-1c was measured. Results showed that hepatic SREBP-1c was activated in mice fed with fructose solution. Fatty acid synthase (fas) and acetyl-CoA carboxylase (acc), two target genes of SREBP-1c, were up-regulated. Fructose-evoked hepatic SREBP-1c activation seemed to be associated with insulin-induced gene (Insig)-1 depletion. An ER stress and unfolded protein response (UPR), as determined by an increased glucose-regulated protein (GRP78) expression and an increased eIF2α and PERK phosphorylation, were observed in liver of mice fed with fructose solution. Phenylbutyric acid (PBA), an ER chemical chaperone, not only significantly attenuated ER stress, but also alleviated fructose-induced hepatic Insig-1 depletion. PBA inhibited fructose-evoked hepatic SREBP-1c activation and the expression of SREBP-1c target genes, and protected against hepatic lipid accumulation. In conclusion, ER stress contributes, at least in part, to hepatic SREBP-1c activation and lipid accumulation in fructose-evoked NAFLD.     

(‐)‐Epigallocatechin‐3‐gallate and atorvastatin treatment down‐regulates liver fibrosis‐related genes in non‐alcoholic fatty liver disease

Non‐alcoholic fatty liver disease (NAFLD) and associated advanced liver diseases have become prevalent conditions in many countries and are associated with increased mortality. Gene expression profiles in NAFLD have been examined recently but changes in expression elicited by chemical compound treatments have not been investigated. Since (‐)‐Epigallocatechin‐3‐gallate (EGCG) and atorvastatin (ATST) exhibit similar efficacy in NAFLD models, we reasoned that some common key genes might alter after treatment of EGCG and ATST. Accordingly, we applied integrated bioinformatics analyses of RNA microarray data from EGCG and ATST treatment groups compared to controls in a NAFLD phenotypic mouse model. Using differential expression (DE) analysis, Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis, Gene Set Enrichment Analysis (GSEA) and ClueGO enrichment, shared EGCG and ATST down‐regulated pathways were identified which included extracellular matrix (ECM)‐receptor interaction and protein processing in endoplasmic reticulum (ER). To refine key genes associated with liver fibrosis, a human NAFLD signature derived from patients of different fibrosis stages was analyzed. The results showed that fibrosis‐related genes Col1a1, Col1a2, Col3a1 and Col6a3 were significantly down‐regulated. These four genes were further validated as down‐regulated in an independent mouse NAFLD dataset. We conclude that EGCG and ATST treatment results in the significant down‐regulation of genes related to liver fibrosis.     

炎症小体介导的细胞焦亡在非酒精性脂肪肝病中的作用及机制

非酒精性脂肪肝病包含单纯性脂肪肝、非酒精性脂肪肝炎和肝硬化等一系列病变,是造成肝硬化、肝细胞癌症的主要因素和肝脏器官移植的重要诱因。非酒精性脂肪肝的发病机制尚不明确,除了加强运动、改善饮食习惯外,目前尚无公认有效的药物治疗方式。细胞焦亡是一种新发现的程序性细胞死亡方式,依赖于天冬氨酸特异性半胱氨酸蛋白酶1（caspase-1）或caspase-11等介导的炎性小体的激活。细胞焦亡过程中常伴有炎症反应的发生,而炎症小体则是细胞产生焦亡和炎症反应所必需的多聚体蛋白复合物,其主要功能是活化caspase-1,从而间接调控炎症因子白介素1（IL-1）和IL-18的表达和分泌。最近的研究表明,细胞焦亡和炎症小体在非酒精性脂肪肝病的发生发展中起重要作用。针对该领域的最新研究进行综述,以期为非酒精性脂肪肝的防治提供新的科学认识和信息。     

ω-3多不饱和脂肪酸治疗非酒精性脂肪性肝病的研究进展

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是由多种危险因素,如营养过剩、胰岛素抵抗(insulin resistance,IR)及相关代谢紊乱等诱导的慢性肝损伤,是代谢综合征在肝脏的病理表现。其病程的进展表现为非酒精性单纯性脂肪肝(nonalcoholic simple fatty liver,NAFL)、非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)、脂肪性肝纤维化和脂肪性肝硬化。NAFLD患病率逐年升高,已成为我国最常见的慢性肝病之一。NAFLD的治疗主要为增加运动、健康饮食等基础治疗,药物治疗尚未达成共识。ω-3多不饱和脂肪酸(ω-3 polyunsattrated fatty acids,ω-3PUFAs)具有调节血脂的功能。NAFLD患者ω-3PUFAs水平较低,增加饮食中的ω-3PUFAs可以延缓病情进展,改善肝脏脂代谢的失衡和肝细胞的炎性损伤。本文主要就ω-3PUFAs对NAFLD治疗的研究进展作一综述。     

非酒精性脂肪性肝病患者焦虑情绪障碍的调查

目的 探讨非酒精性脂肪性肝病(NAFLD)患者胰岛素抵抗及焦虑情绪障碍的发生情况.方法 选择未使用药物治疗的NAFLD患者(NAFLD组)及体检健康者(对照组)各87例.检测肝脏功能、空腹血糖、空腹胰岛素、血脂,计算胰岛素抵抗指数,并进行焦虑状态/特性询问表测试.结果 NAFLD组和对照组焦虑状态/特性阳性率分别为64.3%(56例)和17.2%(16例),组间差异有统计学意义(P＜0.05);NAFLD组的空腹血糖、胰岛素、胰岛素抵抗指数分别为(7.03±2.67)mmol/L、(12.8±4.3)mU/L、(3.19±0.84),与对照组[分别为(4.97±0.68)mmol/L、(6.4±2.3)mU/L、(1.86±0.78)]比较,差异均有统计学意义(P＜0.05).结论 焦虑情绪障碍会引起或加重胰岛素抵抗,进而会影响NAFLD的发生、发展.

Abstract：

Objective To investigate the effects of insulin resistance and anxiety emotional disorders in nonalcoholic fatty liver disease (NAFLD). Methods A total of 87 cases with NAFLD and 87 healthy cases were selected.The level of liver function, fasting blood glucose, fasting insulin, blood fat were tested and insulin resistance index were analyzed with anxiety/characteristics questionnaire. Results Anxiety / feature-positive rate of NAFLD group was 64.3%, healthy state group was 17.2%, (P ＜0.05); Fasting plasma glucose, insulin, hpids, liver function,HOMA-IR of NAFLD group [(7.03 ±2.67) mmol/L, (12.8 ±4.3)mU/L, (3.19 ±0.84)% ,respectively] were higher than those of the control group [(4.97 ± 0.68 ) mmol/L, (6.4 ± 2.3 ) mU/L, ( 1.86 ± 0.78 )%]. Conclusion Anxiety emotional disorders can cause or aggravate insulin resistance(IR). IR may play an important role in the development of NAFLD.     

Impairment of reproductive function in a male rat model of non-alcoholic fatty liver disease and beneficial effect of N-3 fatty acid supplementation

Non-alcoholic fatty liver disease (NAFLD) is closely associated with reduced levels of testosterone, which may affect fertility. Herein, we investigated whether NAFLD impairs the reproductive function of male rats. Male Sprague-Dawley rats were fed a high fat diet (HFD) until they developed NAFLD. N-3 polyunsaturated fatty acid (PUFA) was then given for 4 weeks to prevent hepatic steatosis. Testes weight and serum and testicular testosterone were significantly lower in rats with NAFLD compared with healthy controls. Testicular pathological changes in NAFLD rats included markedly reduced sperm number and motility, and the number of apoptotic spermatogenic cells was higher, which was consistent with a reduction in the number of tetraploid cells. Breeding experiments indicated that paternal NAFLD affected neither the sperm morphology nor the development of fetuses and offspring, but did prolong the days required for insemination. However, administration of N-3 PUFA alleviated the impairment of reproductive function. These results suggest that NAFLD impairs reproductive function in male rats by decreasing testicular testosterone synthesis, and N-3 PUFA treatment may have a beneficial therapeutic effect.     

缬沙坦胶囊治疗伴有非酒精性脂肪肝的高血压患者的疗效观察

目的探讨缬沙坦胶囊治疗伴有非酒精性脂肪肝（NAFLD）的高血压患者的疗效。方法将符合纳入标准患者随机分成试验组和对照组。试验组给予缬沙坦胶囊;对照组给予氨氯地平片。比较两组血压、肝脏超声、肝功能、血脂、胰岛素抵抗指数（RI）的差别及临床疗效。结果缬沙坦胶囊组总有效率（93.24%）显著高于对照组（81.08%）,差异有统计学意义（χ^2=4.891,P=0.027）;治疗后,试验组谷丙转氨酶、胆固醇、甘油三酯、低密度脂蛋白及RI均显著低于对照组,差异有统计学意义（P〈0.05）。结论缬沙坦胶囊治疗伴有NAFLD的高血压患者具有更好疗效。     

Naltrexone changes the expression of lipid metabolism‐related proteins in the endoplasmic reticulum stress induced hepatic steatosis in mice

Endoplasmic reticulum (ER) stress is closely associated with several chronic diseases such as obesity, atherosclerosis, type 2 diabetes, and hepatic steatosis. Steatosis in hepatocytes may also lead to disorders such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), fibrosis, and possibly cirrhosis. Opioid peptides are involved in triglyceride and cholesterol dysregulation. Naltrexone also attenuates ER stress induced hepatic steatosis in mice. In this study, we evaluated the effects of naltrexone on the expression of lipid metabolism‐related nuclear factors and enzymes in the ER stress induced hepatic steatosis. C57/BL6 mice received saline, DMSO and naltrexone as control groups. In a fourth group, ER stress was induced by tunicamycin (TM) injection and in the last group, naltrexone was given before TM administration. Histopathological evaluations, real‐time RT‐PCR and western blot were performed. We found that GRP78, IRE1α, PERK and ATF6 gene expression and steatosis significantly reduced in naltrexone treated animals. Naltrexone alleviated the gene and protein expression of SREBP1c. Expression of ACAT1, apolipoprotein B (ApoB) and PPARα also increased after naltrexone treatment. In conclusion, this study, for the first time, shows that naltrexone has a considerable role in attenuation of ER stress‐induced liver injury.     

非肥胖非糖尿病高血压患者伴发非酒精性脂肪性肝病的危险因素分析

目的探讨非肥胖、非糖尿病的原发性高血压(EH)患者伴发非酒精性脂肪性肝病(NAFLD)的患病率及其危险因素。方法 325例非肥胖、非糖尿病型EH患者住院期间经腹部超声检查和采集病史筛查NAFLD,观察其患病率、肝功酶学异常的比例及其危险因素。结果非肥胖、非糖尿病EH患者伴发NAFLD患者发生率为28.0%(91/325)。NAFLD组男性高于非NAFLD组,差异有统计学意义(P<0.05)。多因素Logistic回归分析中,男性是非肥胖、非糖尿病EH患者NAFLD的独立危险因素。结论非肥胖、非糖尿病EH患者伴NAFLD的发生与性别密切相关,男性是其独立危险因素。     

A small molecule UPR modulator for diabetes identified by high throughput screening

Unfolded protein response (UPR) is a stress response that is specific to the endoplasmic reticulum (ER). UPR is activated upon accumulation of unfolded (or misfolded) proteins in the ER's lumen to restore protein folding capacity by increasing the synthesis of chaperones. In addition, UPR also enhances degradation of unfolded proteins and reduces global protein synthesis to alleviate additional accumulation of unfolded proteins in the ER. Herein, we describe a cell-based ultra-high throughput screening (uHTS) campaign that identifies a small molecule that can modulate UPR and ER stress in cellular and in vivo disease models. Using asialoglycoprotein receptor 1 (ASGR) fused with Cypridina luciferase (CLuc) as reporter assay for folding capacity, we have screened a million small molecule library and identified APC655 as a potent activator of protein folding, that appears to act by promoting chaperone expression. Furthermore, APC655 improved pancreatic β cell viability and insulin secretion under ER stress conditions induced by thapsigargin or cytokines. APC655 was also effective in preserving β cell function and decreasing lipid accumulation in the liver of the leptin-deficient (ob/ob) mouse model. These results demonstrate a successful uHTS campaign that identified a modulator of UPR, which can provide a novel candidate for potential therapeutic development for a host of metabolic diseases.     

立普妥联合甘乐对老年非酒精性脂肪肝患者血生化及肝脏超声的影响

目的观察阿托伐他汀(立普妥)联合复方二氯醋酸二异丙胺(甘乐)对老年非酒精性脂肪肝(NAFLD)患者血生化及肝脏超声的影响。方法 2010年9月至2012年1月我院NAFLD患者106例,口服立普妥(10 mg,每晚1次)、甘乐(40 mg,3次/d),3个月为1个疗程。观察治疗前后TG、TC、ALT、AST及肝脏超声变化。结果治疗3个月后,TG、TC、ALT、AST及肝脏超声均显著改善(P<0.01)。结论立普妥联合甘乐可使老年NAFLD患者肝功能、血脂及肝脏超声影像显著改善,且无明显不良反应。     

非酒精性脂肪性肝病兔肝功能影响因素探讨

目的以丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)为肝功能观察指标,探讨非酒精性脂肪性肝病(NAFLD)兔肝功能影响因素。方法 40只日本大耳白兔随机分为重度NAFLD模型组(重度组)、轻度NAFLD模型组(轻度组)、空白对照组(对照组)。重度组每只兔给予高脂饲料160 g/d,轻度组给予高脂饲料80 g/d+普通饲料80 g/d,对照组给予普通饲料160 g/d。饲养13周。饲养前耳中动脉采血5 mL于肝素管,离心、血浆保存于-20℃冰柜中。实验结束10%水合氯醛耳缘静脉麻醉,腹主动脉抽血5 mL于肝素管,离心、血浆保存于-20℃冰柜中。全部血浆按照设备、试剂操作常规检测甘油三酯、胆固醇、血糖、ALT、AST。在肝脏同一部位取1.5 cm×1.5 cm×1.5 cm组织1块,浸泡于10%甲醛固定液中固定,脱水石蜡包埋,切片,苏木素-伊红(HE)染色,光镜下观察肝脏组织形态学改变。结果①甘油三酯、胆固醇:饲养前重度组、轻度组、对照组甘油三酯、胆固醇比较差异无统计学意义(P>0.05)。饲养后甘油三酯、胆固醇重度组分别为(32.1±1.2)、(6.0±2.1)mmol/L,轻度组分别为(18.3±2.1)、(4.4±1.9)mmol/L,与饲养前比较差异有统计学意义(P<0.01);重度组高于轻度组,差异有统计学意义(P<0.01)。②血糖:饲养前重度组、轻度组、对照组血糖比较差异无统计学意义;饲养后重度组(11.0±1.2)mmol/L、轻度组(9.2±2.0)mmol/L与饲养前比较差异有统计学意义(P<0.01和<0.05);重度组高于轻度组,差异有统计学意义(P<0.05)。③ALT、AST:饲养前重度组、轻度组、对照组ALT、AST差异无统计学意义(P>0.05),饲养后重度组ALT(122±9)U/L、AST(126±9)U/L,轻度组ALT(83±7)U/L、AST(85±9)U/L,与对照组ALT(71±7)U/L、AST(72±4)U/L比较差异有统计学意义(P<0.01),重度组与轻度组比较差异有统计学意义(P<0.01)。④肝脏病理学:重度组重度NAFLD,轻度组轻度至中度NAFLD,对照组正常肝脏。结论 NAFLD兔肝功能损害与血糖、甘油三酯、胆固醇代谢紊乱及NAFLD程度相关。     

蛹油α-亚麻酸乙酯胶丸治疗非洒精性脂肪性肝病患者的临床疗效观察

目的：观察蛹油α-亚麻酸乙酯胶丸治疗非酒精性脂肪性肝病（NAFLD）患者的临床疗效。方法：观察治疗前后肝功能、血脂、瘦素、胰岛素抵抗指数（HOMA—IR）的变化。结果：治疗前后肝功能、血脂有显著性下降（P〈0.05）．瘦素、HOMA—IR水平下降（P〈0.05）,治疗组与对照组比较有统计学意义。结论：蛹油α-亚麻酸乙酯胶丸通过[]改善靶组织对胰岛素的敏感性．减轻非酒精性脂肪性肝病的胰岛索抵抗,调节血脂,从而减轻非酒精性脂肪性肝病的肝损害,为临床治疗提供理论依据。     

Hyperuricaemia and non-alcoholic fatty liver disease (NAFLD): a relationship with implications for vascular risk?

Both elevated levels of uric acid and non-alcoholic fatty liver disease (NAFLD) have been associated with increased vascular risk. Furthermore, certain drugs (e.g. lipid and blood pressure lowering) that decrease)cardiovascular risk and improve/preserve renal function were shown to influence serum uric acid (SUA) levels and/or NAFLD. A link between hyperuricaemia and NAFLD has also been suggested. This review considers the associations between hyperuricaemia, NAFLD and vascular risk. We also discuss the effects of different drug treatments on SUA and NAFLD. As NAFLD is a very common condition, future work in this field is needed with regard to a more practical definitive diagnosis, evidence- based treatments and a better understanding of the possible links between NAFLD, elevated SUA levels, cardiovascular disease and chronic kidney disease. Whether treating hyperuricaemia and NAFLD will translate into a reduced risk of vascular events requires further investigation.     

中药蛤蚧对非酒精性脂肪肝内质网应激的影响分析

目的：探析中药蛤蚧对非酒精性脂肪肝内质网应激的影响。方法以60只健康雄性C57BL/6小鼠进行研究,高脂饲料喂养的小鼠纳入模型组(n=30),普通饲料标准喂养的小鼠纳入正常对照组(n=30)。模型组中应用中药蛤蚧的小鼠为A组,生理盐水为B组;正常对照组中应用中药蛤蚧的小鼠为C组,生理盐水组为D组。比较建模前后、喂药前后小鼠肝脏内质网应激,具体用丙二醛( MDA)、还原性谷胱甘肽( GSH)及氧化型谷胱甘肽( GSSG)等指标。结果两组建模前MDA、GSH及GSSG的差异无统计学意义(P>0．05),建模后正常对照组各项指标无明显变化(P>0．05);建模后模型组MDA、GSSG升高、GSH降低(P<0．05)。 B、C、D组喂药前后差异无统计学意义(P>0．05);A组(中药蛤蚧)喂药后MDA与GSSG均明显降低、GSH升高(P<0．05)。结论中药蛤蚧具有调节脂质代谢、保肝、抗炎、抗氧化、增强免疫、提高细胞对内质网应激忍耐性等作用,在非酒精性脂肪肝中的应用可通过发挥降脂作用启动肝细胞内质网胁迫机制,最终保护肝脏组织。     

老年人非酒精性脂肪性肝病与血脂血糖水平及体重指数的关系

目的探讨老年人非酒精性脂肪性肝病(NAFLD)与血脂血糖水平、体重指数等指标的关系。方法298例老年人按非酒精性脂肪性肝病诊断标准分为脂肪肝组(114例)和非脂肪肝组(184例),观察临床表现,检测血脂、血糖、体重指数、肝功能等指标并进行分析。结果脂肪肝组血脂、血糖水平、体重指数明显增高,和非脂肪肝组比较差异有显著性(P相似文献   

Are statins ‘IDEAL’ for non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and cause of elevated serum liver enzyme activities in the developed world1. Obesity, diabetes mellitus (DM), and dyslipidaemia, common components of the metabolic syndrome (MetS), are frequently associated with NAFLD; 75–100% of patients with MetS or DM have NAFLD2. NAFLD is characterized by hepatic triglyceride (TG) infiltration in the absence of alcohol abuse or chronic liver disease1. NAFLD includes a spectrum of conditions varying from steatosis to steatosis with inflammation [steatohepatitis (NASH)], necrosis, fibrosis or cirrhosis that rarely progresses to hepatocellular carcinoma3. NAFLD and NASH are the hepatic manifestations of MetS and are associated with increased cardiovascular disease (CVD) risk4. Most NAFLD/NASH patients die from CVD rather than from liver disease4,5. There is no universally accepted treatment for NAFLD1-5.     

健脾化痰祛瘀汤治疗非酒精性脂肪肝对肝功能及血脂水平的影响

目的 分析健脾化痰祛瘀汤治疗非酒精性脂肪肝对肝功能及血脂水平的影响。方法 110例非酒精性脂肪肝患者按照随机数表法分为观察组和对照组,各55例,对照组给予辛伐他汀治疗,观察组给予健脾化痰祛瘀汤治疗,治疗4周后,比较两组患者的治疗效果、肝功能及血脂水平。结果观察组总有效率（98.2%）高于对照组（52.7%）,观察组TC、TG、ALT、AST均低于对照组,差异均具有统计学意义（P〈0.05）。结论 健脾化痰祛瘀汤治疗非酒精性脂肪肝能有效改善患者肝功能,提高临床疗效,具有积极的应用价值。