非酒精性脂肪性肝病分子机制研究进展

非酒精性脂肪性肝病(NAFLD)是一种以肝细胞脂肪变性和脂质沉积为特征,但无过量饮酒史的临床综合征。NAFLD疾病谱包括非酒精性单纯性脂肪肝、非酒精性脂肪性肝炎(NASH)、NASH相关肝纤维化和肝硬化。NAFLD的发病机制较为复杂,至今尚未完全阐明。本文就近年NAFLD分子机制研究的新进展,包括胰岛素抵抗(IR)、肝脂肪变性、氧化应激等方面作一综述。     

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。     

胰岛素抵抗与非酒精性脂肪性肝病

非酒精性脂肪性肝病（NAFLD）是指除外酒精和其他明确的损肝因素所致的,以弥漫性肝细胞大泡性脂肪变为主要特征的临床病理综合症,包括单纯性脂肪肝、脂肪性肝炎、脂肪性肝纤维化和脂肪性肝硬化4个病理过程。随着人们生活水平的提高和生活方式的改变,特别是饮食结构的变化和体力活动的减少,NAFLD的发病率呈现逐年升高的趋势。     

改善胰岛素抵抗治疗NAFLD/NASH的循证证据

非酒精性脂肪性肝病/非酒精性脂肪性肝炎(NAFLD/NASH)是指除外酒精和其他明确的肝损伤因素所致的以肝细胞脂肪沉积为特征的临床病理综合征。胰岛素抵抗(IR)与NAFLD/NASH的发病密切相关,因此改善IR或许可以减轻肝损伤。多项随机对照临床试验显示胰岛素增敏剂和逐渐减轻体质量(饮食疗法或体育锻炼等)对NAFLD的治疗有一定作用,但长期疗效尚不明确。本文对近年关于改善IR治疗NAFLD/NASH的临床试验作一综述。     

罗格列酮联合还原型谷胱甘肽对NAFLD大鼠胰岛素及胰岛素信号转导相关蛋白的影响

目的研究罗格列酮联合还原型谷胱甘肽对非酒精性脂肪性肝病(NAFLD)大鼠胰岛素以及胰岛素信号转导相关蛋白表达的影响。方法建立NAFLD大鼠模型,设计罗格列酮单独和联合还原型谷胱甘肽治疗组、模型组、正常对照组,应用HE染色、免疫组织化学、ELISA方法比较各组大鼠血清和胰腺组织中胰岛素以及胰岛素信号转导相关蛋白[胰岛素受体(IR)和胰岛素受体底物-2(IRS-2)]表达水平。结果模型组血清胰岛素水平较正常对照组明显上升(P0.01),而IR和IRS-2水平明显下降(P0.01);药物干预组胰岛素水平较模型组明显下降(P0.05),罗格列酮组IR水平较模型组及联合用药组明显上升(P0.05),但其他指标在药物组和模型组之间差异无统计学意义。模型组大鼠胰腺组织内胰岛素表达强度明显高于正常组(P0.05),药物组胰岛素表达强度明显低于模型组(P0.05),而IR、IRS-2表达强度则明显高于模型组(P0.05),两药物组之间差异无统计学意义。结论NAFLD大鼠血清和胰腺组织内胰岛素I、R和IRS-2含量均发生明显变化,罗格列酮单独或联合还原型谷胱甘肽能明显下调血清及胰腺组织内胰岛素表达,同时不同程度提高血清或胰腺组织内IR和IRS-2含量,但联合用药未显示协同作用。     

奥利司他对肥胖伴非酒精性脂肪性肝病的作用及危险因素的影响

探讨奥利司他(orlistat)在治疗肥胖伴非酒精性脂肪性肝病(NAFLD)中的作用。选择体重指数(BM I)在25和32之间,伴有肝功能异常的NAFLD患者30例,给予奥利司他120mg,日三次口服,治疗24周。治疗结束后,所有患者的体重、BM I、腰围、腰臀比及血压明显下降(P值均<0.001);肝功能中ALT、AST、GGT、Tch、TG及IR与治疗前相比有明显改善(P值均<0.001);肝脏CT密度值及肝/脾CT密度比值均显著增加(P值均<0.001)。奥利司他可有效地减少NAFLD患者肝脏内脂肪沉积,改善肝功能和相关代谢综合征,可作为肥胖伴NAFLD的药物治疗选择。     

核因子-κB与非酒精性脂肪性肝病

KB是一类重要的转录调控因子．通过调节免疫和炎症相关因子的表达在炎症和免疫反应中起枢纽作用。NF-KB与NAFLD的关系密切，对NF-KB的研究可能为探讨NAFLD的发病机制和治疗方案提供新的线索。本文就NF-KB的生物学特性、功能及其在NAFLD发生、发展中的作用作一综述。     

重视非酒精性脂肪性肝病胰岛素抵抗的防治

胰岛素抵抗广泛存在于非酒精性脂肪性肝病发生、发展的各个环节.胰岛素抵抗的存在不仅影响非酒精性脂肪性肝病的进展,还提高肝细胞对损肝因素的敏感性,影响药物治疗的效果.重视非酒精性脂肪性肝病胰岛素抵抗的诊断和治疗,将有益于改善非酒精性脂肪性肝病的预后,提高药物治疗效果.中医药治疗胰岛素抵抗已经显示了一些特色和优势,在加强患者科学管理,重视生活方式干预的基础上,开展对非酒精性脂肪性肝病胰岛素抵抗证候病机的研究,加强对有效方药的科学评价并积极探索其作用机制,将有助于提高中医药防治胰岛素抵抗的研究水平.     

胰岛素抵抗与非酒精性脂肪性肝病

胰岛素抵抗(IR)在非酒精性脂肪性肝病(NAFLD)发病过程中起至关重要的作用.目前大量研究支持NAFLD“二次打击”学说,初次打击IR引起肝细胞单纯性脂肪变性,二次打击脂肪变的肝细胞发生成脂性转化,诱导炎性反应、氧化应激、内质网应激的发生,损伤肝细胞功能,加重IR,促进NAFLD发展.     

非酒精性脂肪性肝病患者血清瘦素与胰岛素抵抗的关系

目的通过检测非酒精性脂肪性肝病(NAFLD)患者血清瘦素(Lp)的水平,探讨血清瘦素与胰岛素抵抗的关系。方法应用RIA检测30例NAFLD患者及30例对照者血清Lp水平,并检测空腹血糖、总胆固醇、甘油三酯、C-肽、胰岛素、体质指数等临床指标,分析Lp与胰岛素抵抗、血脂及非酒精性脂肪性肝病的关系。结果 NAFLD患者的Lp、BMI、胰岛素及胰岛素抵抗指数(HOMAIR)均显著高于对照组(P0.05)。男、女NAFLD患者Lp水平均高于男、女对照组(P0.05)。以HOMAIR为因变量,Lp、BMI、C-肽、总胆固醇及甘油三酯作为自变量,进行多元逐步回归分析,瘦素为影响IR的主要因素。结论 Lp可促进胰岛素抵抗,提示Lp与NAFLD有密切的关系。     

Effect of Aerobic and Resistance Exercise Training on Liver Enzymes and Hepatic Fat in Iranian Men With Nonalcoholic Fatty Liver Disease

Background:

Nonalcoholic fatty liver disease (NAFLD) has different prevalence rates in various parts of the world and is a risk factor for diabetes and cardiovascular disease that could progress to nonalcoholic steatohepatitis, cirrhosis, and liver failure.

Objectives:

The current study aimed to investigate the effect of Aerobic Training (AT) and resistance training (RT) on hepatic fat content and liver enzyme levels in Iranian men.

Patients and Methods:

In a randomized clinical trial study, 30 men with clinically defined NAFLD were allocated into three groups (aerobic, resistance and control). An aerobic group program consisted of 45 minutes of aerobic exercise at 60% - 75% maximum heart rate intensity, a resistance group performed seven resistance exercises at intensity of 50% - 70% of 1 repetition maximum (1RM ) and the control group had no exercise training program during the study. Before and after training, anthropometry, insulin sensitivity, liver enzymes and hepatic fat were elevated.

Results:

After training, hepatic fat content was markedly reduced, to a similar extent, in both the aerobic and resistance exercise training groups (P ≤ 0.05). In the two exercise training groups, alanine amino transferase and aspartate amino transferase serum levels were significantly decreased compared to the control group (P = 0.002) and (P = 0.02), respectively. Moreover, body fat (%), fat mass (kg), homeostasis model assessment insulin resistance (HOMI-IR) were all improved in the AT and RT. These changes in the AT group were independent of weight loss.

Conclusions:

This study demonstrated that RT and AT are equally effective in reducing hepatic fat content and liver enzyme levels among patients with NAFLD. However, aerobic exercise specifically improves NAFLD independent of any change in body weight.     

脂类对非酒精性脂肪性肝病发生的影响

作为代谢综合征重要组分之一的非酒精性脂肪性肝病（NAFLD）在肥胖、2型糖尿病和高脂血症人群中有着相当高的发病率．如不予及时干预,将给人类健康带来巨大威胁。脂质在肝脏异常异位蓄积是NAFLD发生的主要原因,其中起重要作用的脂类主要包括三酰甘油、胆固醇和脂肪酸。这些脂质来源各异,分别在NAFLD肝细胞脂肪变性的不同阶段发挥作用。本文就不同脂类在NAFLD发生中的作用作一综述。     

调脂积冲剂对脂肪肝大鼠胰岛素抵抗的影响

目的——探讨调脂积冲剂防治脂肪肝的有效性、可靠性,及其对胰岛素抵抗的影响。方法——采用酒精合并高脂乳剂建立大鼠脂肪肝模型,以易善复和六味地黄丸为阳性对照,检测TC、TG、HDL-C、LDL-C、ALT、GGT和FBG,采用酶联免疫法测定血清胰岛素含量。胰岛B细胞功能评价采用稳态模式评估法,即胰岛素抵抗指数（HOMA-IR）=（FBG）·FINS／22．5。结果——调脂积冲剂能降低ALT、CGT、TC、TG、LDL-C、FBC和FINS的含量,降低胰岛素抵抗指数。讨论——调脂积冲剂能有效防治脂肪肝,其机制可能与其改善胰岛素抵抗有关。     

活血化瘀化痰利湿法对肥胖性脂肪肝大鼠胰岛素敏感指数和肿瘤坏死因子的影响

目的:探讨活血化瘀、化痰利湿法改善肥胖性脂肪肝大鼠胰岛素抵抗(IR)状态的机制,为临床中医辨证治疗脂肪肝提供实验依据。方法:32只健康雄性SD大鼠随机分为正常组、造模组、西药组、中药组。除正常组饲以普通饲料外,其余各组均饲以高脂饲料。造模4周后,上述4组分别以生理盐水、生理盐水、0.08％东宝肝泰混悬液、中药煎剂灌胃。实验第16周测定血清和脂肪组织中肿瘤坏死因子-α(TNF-α)及血糖、胰岛素等。并取肝组织标本病理切片。结果:①胰岛素敏感指数(ISI):治疗组较造模组显著提高(P<0.05);中药组与正常组相比无显著性差异(P>0.05),与西药组相比有明显差异性(P<0.05)。②血清和脂肪组织TNF-α:治疗组与造模组相比有显著性差异(P<0.01),治疗组与正常组相比无明显差异性(P>0.05),中药组与西药组相比无明显差异(P>0.05)。③肝脏病理切片:正常组大鼠肝脏无异常病变、模型组大鼠肝脏均出现不同程度的肝脂变。各治疗组大鼠肝脏脂变程度明显减轻。结论:活血化瘀、化痰利湿法能够降低脂肪细胞TNF-α的表达,提高肥胖性脂肪肝大鼠ISI,改善IR状态;改善肝细胞的病理损伤状况,从而达到抗脂肪肝的目的。     

The Effect of Pioglitazone and Metformin on Liver Function Tests,Insulin Resistance,and Liver Fat Content in Nonalcoholic Fatty Liver Disease: A Randomized Double Blinded Clinical Trial

Background

Non-alcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of insulin resistance (IR) syndrome. The effect of insulin sensitizers on liver function tests and metabolic indices in NAFLD patients is a matter of debate.

Objectives

The aim of study was to compare the effects of two different insulin sensitizers, pioglitazone, and metformin, on liver function tests (LFT), lipid profile, homeostasis model assessment-IR (HOMA-IR) index, and liver fat content (LFC) in NAFLD patients.

Materials and Methods

This double blind clinical trial was performed on patients who were referred to a gastroenterology clinic with evidence of fatty liver in ultrasonography. After excluding other causes, participants with persistent elevated alanine aminotransferase (ALT) levels and “NAFLD liver fat score” greater than -0.64 were presumed to have NAFLD and were enrolled. They were randomly assigned to take metformin (1 g/day) or pioglitazone (30 mg/day) for four months. Fasting serum glucose (FSG), ALT, aspartate aminotransferase (AST), alkaline phosphatase (ALP), triglyceride, cholesterol (CHOL), high and low density lipoprotein (HDL, LDL), HOMA-IR, and LFC were checked at the baseline, two and four months post-treatment. LFC was measured by a validated formula.

Results

Eighty patients (68 males) with mean age of 35.27 (± 7.98) were included. After 2 months, LFT was improved significantly in the pioglitazone group and did not change in the metformin group. After four months, both medications significantly decreased serum levels of LFT, FSG, CHOL, LDL, HOMA-IR, and LFC, and increased serum level of HDL. No statistically significant differences were seen between the two treatment groups with regard to the changes of laboratory parameters and LFC from baseline to four months post-treatment.

Conclusions

During the four months, the use of metformin (1 g/day) and pioglitazone (30 mg/day) were safe and might have equally affected LFT, HOMA-IR, lipid profile, and LFC in NAFLD patients.     

Relationship of Insulin Resistance to Protein-Energy Malnutrition in Patients with Alcoholic Liver Cirrhosis: Effect of Short-Term Nutritional Support

Protein-energy malnutrition (PEM) and insulin resistance (IR) are common features of alcoholic liver cirrhosis (ALC). In order to determine a relationship between them, nutritional status and glucose homeostasis were studied in 26 patients with ALC. Nutritional status was assessed through dietary, anthropometric, and biological parameters. An IR index (M/I) was obtained from the euglycemic insulin clamp technique. M/I was significantly correlated with accurate markers of PEM (albumin, transthyretin, and retinol-binding protein) but not with other markers of liver dysfunction. Nine patients were studied before and after nutritional support: M/I was significantly improved as were serum markers of PEM. Other markers of liver dysfunction were also significantly improved. These findings suggest that PEM could be responsible, in part, for IR in patients with ALC who are frequently malnourished. Moreover, nutritional support improved insulin sensitivity in these patients.     

肠道微生态失衡致非酒精性脂肪性肝病发病机制的研究进展

非酒精性脂肪性肝病（NAFLD）已成为一种常见的慢性肝病。近年肠道微生态失衡致NAFLD发病的机制研究已成为一个新的热点。国内外文献已报道相关发病机制可能包括干扰代谢、促进胰岛素抵抗、产生毒性代谢产物、增加肠壁通透性、激活肠道免疫、加重肝脏脂质氧化和氧化应激、激活肝脏免疫炎症损伤和肝纤维化等。而NAFLD发展到一定阶段后又可反过来影响肠道微生态,形成恶性循环。本文就肠道微生态失衡致NAFLD发病机制的研究进展作一综述。