瘦素在非酒精性脂肪肝发病中的作用机制研究进展

非酒精性脂肪肝最早由Ludwig[1]于1980年定义,指女性肥胖症伴2型糖尿病的患者虽然没有饮酒史但肝脏病理类似于酒精性肝炎的综合征。现在非酒精性脂肪肝是一个临床病理名称,包括肝细胞的脂肪沉积、脂肪性肝炎、肝纤维化和肝硬化。非酒精性脂肪肝是一个进展的过程[2]。随着膳食结构和生活方式的改变,人群非酒精性脂肪肝的发病率逐年升高,在一项大样本的流行病学调查中,Szczepaniak[3]等通过核磁共振发现超过1/3的调查对象存在肝细胞的脂肪沉积。对非酒精性脂肪肝的发生机制研究也逐渐被重视。目前非酒精性脂肪肝被认为是全身代谢综合征的一个…     

非酒精性脂肪肝的病因和发病机制

一、基本概念 狭义的脂肪肝是指肝细胞内中性脂肪——三酰甘油(TG)异常增多的病理状态,而由脂代谢酶遗传性缺陷所致的类脂质沉积病,以及胺碘酮、环已哌啶等药物所致的肝细胞溶酶体磷脂沉积病不     

非酒精性脂肪肝患者视黄醇结合蛋白4与胰岛素抵抗的关系

目的探讨非酒精性脂肪肝(NAFLD)患者血清视黄醇结合蛋白4(RBP-4)与胰岛素抵抗(IR)的关系。方法选择NAFLD患者150例,年龄、性别相匹配的健康对照150例,检测血清RBP-4、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、空腹血糖(FPG)、空腹胰岛素(FINS),以及身高、体重,计算体重指数(BMI)、稳态模型胰岛素抵抗指数(HOMA-IR)。结果 NAFLD组血清RBP-4水平〔(20.30±10.50)ng/ml〕明显低于对照组〔(25.14±11.44)ng/ml,P<0.01〕;血清RBP-4水平与BMI、FPG、FINS和HOMA-IR呈负相关(r分别为-0.171、-0.152、-0.180、-0.193,均P<0.01),与HDL-C呈正相关(r=0.147,P<0.05)。回归分析示,HOMA-IR是血清RBP-4的独立的影响因素(β=-1.561,P<0.01)。结论 NAFLD患者血清RBP-4水平降低,且与IR密切相关。     

非酒精性脂肪性肝炎发病机制的实验研究

目的：通过建立大鼠非酒精性脂肪性肝炎（NASH）动物模型,探讨NASH的发病机制。方法：通过持续12周的高脂肪、高胆固醇饮食建立大鼠NASH模型,造模结束时检测模型组及正常组血清转氨酶、游离脂肪酸（FFA）;测定肝匀浆丙二醛（MDA）、超氧化物歧化酶（SOD）、FFA;用免疫组化法标记肝组织细胞色素P450ⅡE1（CYPⅡE1）及溶菌酶（LYZ）免疫阳性细胞－Kupffer细胞。结果：造模大鼠存在血清和肝匀浆FFA升高,肝匀浆脂质过氧化终产物MDA增加,而抗氧化物质SOD减少,肝组织免疫组化示CYPⅡE1呈高表达,Kupffer细胞明显增多。相关分析表明：随着FFA的增加,CYPⅡE1表达增高,脂质过氧化损伤亦增强,并且肝脏炎症、坏死加剧。结论：FFA在NASH的发病机制中起着重要作用;FFA的增加及其所引起的一系列CYPⅡE1高表达、Kupffer细胞激活以及脂质过氧化损伤,共同导致NASH以及肝细胞坏死。     

非酒精性脂肪肝炎发病机制研究现状

非酒精性脂肪肝炎（NASH）是指临床表现和组织学改变与酒精性肝炎非常相似,但无过量饮酒史的一种临床病理综合征,其组织学具有肝细胞变性、气球样变和点状坏死以及混合性炎细胞浸润的特征,可伴Mallory小体和不同程度肝纤维化.实际上,NASH只是非酒精性脂肪性肝病（NAFLD）病程发展的一个阶段,被认为是隐源性肝硬化的原因之一。     

细胞因子在非酒精性脂肪性肝炎发病机制中的作用

随着非酒精性脂肪性肝病发病率的逐年上升及其对健康的危害,包括3种类型:单纯性脂肪肝、脂肪性肝炎和脂肪性肝硬化已受到越来越多的重视,而非酒精性脂肪性肝炎是由单纯性脂肪肝发展为脂肪性肝硬化的必经阶段,了解其发病机制,探讨具有多种生物学效应的细胞因子在非酒精性脂肪性肝炎中的作用,对于弄清其发病机制的多样性有着深刻的意义。     

瘦素在非酒精性脂肪肝中的作用机制

自1994年发现瘦素以来，对瘦素与肥胖及其相关疾病的研究越来越受重视。Zhang Y等认为ob基因结构和序列的改变可以导致肥胖。Considine RV研究认为人类肥胖者，极少数为体内缺乏瘦素，绝大多数表现高瘦素血症，肥胖症患者血浆中瘦素的浓度平均约4倍高：于非肥胖者。非酒精性脂肪性肝病（nonalcoholic fatty liver disease，NAFLD）主要由肥胖、高脂等代谢紊乱所致。在NAFLD的发生发展过程中，瘦素的作用日益受到重视，Tobe K等研究认为瘦素是脂肪肝发生的独立危险因素。     

脂肪细胞因子在非酒精性脂肪肝发病机制中的作用

非酒精性脂肪性肝病是常见的慢性肝病,但其发病机制目前尚不十分清楚,脂代谢异常与胰岛素抵杭可能是其发病的中心环节,瘦素、脂联素和抵抗素等多种脂肪因子在非酒精性脂肪肝的形成、炎性改变及纤维化的过程中发挥了重要作用。     

非酒精性脂肪肝研究新进展

非酒精性脂肪肝(nonalcoholic fatty liver disease,NAFLD)是一种无过量饮酒史,以肝细胞脂肪变性和脂质贮积为特征的临床病理综合征,包括单纯性脂肪肝、脂肪性肝炎、脂肪性肝纤维     

非酒精性脂肪肝的研究进展

非酒精性脂肪肝（NAFLD）是一种无过量饮酒史，但病理学改变类似酒精性脂肪性肝病（AFLD），以肝细胞脂肪变性和脂质贮积为特征的临床病理综合征。其疾病谱包括单纯性脂肪肝、脂肪性肝炎（NASH）、脂肪性肝纤维化和脂肪性肝硬化四个从轻到重的病理阶段。     

2型糖尿病合并非酒精性脂肪性肝病患者血清视黄醇结合蛋白4水平变化及影响因素的研究

目的 研究T2DM合并非酒精性脂肪性肝病（NAFLD）患者血清视黄醇结合蛋白4（RBP4）水平变化.方法 选取单纯T2DM患者（T2DM） 32例,T2DM合并NAFLD者（T2DM＋NAFLD）31例及正常对照（NC）者34名,测定血清RBP4水平,并计算胰岛β细胞功能指数（HOMA-β）及葡萄糖处置指数（DI）.结果 与其他两组比较,T2DM＋ NAFLD组血清RBP4水平最高（P＜0.05或P＜0.01）,而DI最低（P均＜0.01）.且TG、WC、SBP、DI是RBP4的独立影响因素（P均＜0.05）.RBP4是T2DM合并NAFLD独立危险因素（OR=1.142,P=0.057）.结论 血清RBP4在T2DM＋NAFLD组最高,与胰岛β细胞功能密切相关.     

Role of ezetimibe in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum ranging from simple steatosis to steatohepatitis,advanced fibrosis and inflammatory changes.Ezetimibe inhibits cholesterol absorption from the intestinal lumen into enterocytes.The molecular target of ezetimibe is the sterol transporter Niemann-Pick C1-like 1 protein (NPC1L1).Human NPC1L1 is abundantly expressed in the liver and may facilitate the hepatic accumulation of cholesterol.Ezetimibe ex-erts beneficial effects on several metabolic variables.Ezetimibe treatment attenuates hepatic steatosis and is beneficial in terms of NAFLD biochemical markers.The combination of ezetimibe with other interventions may also be beneficial in NAFLD patients.Our group inves-tigated the ezetimibe-orlistat combination treatment in overweight and obese patients with hypercholeste-rolemia,with beneficial effects on NAFLD biochemical markers.These results are promising for patients with NAFLD,who usually have increased cardiovascular disease risk and need a multifactorial treatment.How-ever,it should be mentioned that most results are from animal studies and,although modest elevation of liver function tests may raise the suspicion of NAFLD,none of these tests are sensitive to establish the diagnosis of NAFLD with great accuracy.     

Serum retinol binding protein 4 and nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus

Retinol binding protein 4 (RBP4) is a protein secreted by adipocytes, and closely associated with insulin resistance. Whereas RBP4 is also mainly expressed in hepatocytes as the principal transport protein for retinol (vitamin A) in the circulation, and its pathophysiological role in liver remain unclear. The aim of this paper was to investigate the association between RBP4 and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). Serum RBP4 and adiponectin concentrations were measured by radioimmunoassay in 52 diabetic patients who had NAFLD and 50 sex- and age-matched diabetic patients without any clinical features of liver diseases who had normal liver ultrasonic appearance and normal liver function. Serum RBP4 levels were elevated in diabetic patients with NAFLD (32.0+/-8.9 microg/ml vs. 41.3+/-9.8 microg/ml, p<0.001), while adiponectin decreased (17.4+/-9.3 microg/ml vs. 13.8+/-7.0 microg/ml, p=0.032). Male diabetic patients had higher serum RBP4 concentration and lower serum adiponectin concentration than female diabetic patients (38.5+/-9.9 microg/ml vs. 34.0+/-10.7 microg/ml, p=0.031 and 12.7+/-5.7 microg/ml vs. 20.23+/-9.8 microg/ml, p<0.001, respectively). Multiple logistic regression analysis revealed RBP4 and triglyceride as independent association factors for NAFLD, while the association between serum adiponectin and NAFLD was not significant. Increasing concentrations of RBP4 were independently and significantly associated with NAFLD in diabetic patients. In multiple linear regression analysis, alanine aminotransferase, fasting serum insulin and adiponectin were independent factors for serum RBP4 level. The study demonstrates that retinol binding protein 4 might contribute to the pathogenesis of nonalcoholic fatty liver disease.     

细胞凋亡在非酒精性脂肪性肝病中的作用

非酒精性脂肪性肝病(non-alcoholic fatty liver disease.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征.随着生活水平的提高、生活习惯、饮食结构的改变,肥胖和糖尿病的发病率增加,NAFLD的发病率呈上升趋势,严重危害人民健康.而非酒精性脂肪性肝病的发病机制仍不十分清楚,最近研究表明细胞凋亡及其相关因素Fas系统、TNF家族、Bel-2蛋白家族、Caspases蛋白酶家族、NF-κB、细胞色素C及组织蛋白酶B等在NAFLD中表达异常增多,说明肝细胞凋亡在NAFLD的发生进展中扮演了至关重要角色.本文就这方面的研究进展作一综述.     

库普弗细胞在非酒精性脂肪性肝病中的作用

库普弗细胞(KC)是定居于肝内的单核-巨噬细胞,其表面存在多种受体,可被多种配体激活,通过产生细胞因子、炎症介质和活性氧簇等在多种肝损伤的发病过程中起重要作用。近年的研究显示KC也参与非酒精性脂肪性肝病的发病机制,在胰岛素抵抗、氧应激和炎症过程中起重要作用,因此控制KC的活化将有助于减轻或阻止非酒精性脂肪性肝病的的发展。     

Circulating and liver tissue levels of retinol-binding protein-4 in non-alcoholic fatty liver disease

Aim:  Retinol-binding protein-4 (RBP4) has been proposed as a new adipokine that regulates insulin action in muscles and the liver, and contributes to the pathogenesis of insulin resistance. As non-alcoholic fatty liver disease (NAFLD) is related to insulin resistance, we aimed to evaluate RBP4 levels in the serum and liver of patients with NAFLD.
Methods:  Serum RBP4 was measured in 30 NAFLD patients and 30 matched healthy controls. RBP4 expression in the liver of NAFLD patients was shown by immunohistochemistry.
Results:  Serum RPB4 was significantly lower in NAFLD patients compared with controls (25.15 vs 34.66 µg/mL, P  < 0.001) and there was no correlation with metabolic parameters or insulin resistance. RBP4 liver tissue immunostaining was more extensive and intense in NAFLD liver compared with normal liver and the RBP4 immunohistochemical score was positively correlated with the grade of steatosis, grade of non-alcoholic steatohepatitis activity and stage of fibrosis.
Conclusions:  In NAFLD patients, serum RBP4 was significantly lower as compared with controls and did not correlate with insulin resistance. In contrast, RBP4 liver tissue expression was enhanced and correlated with NAFLD histology.     

Role of liver biopsy in the assessment of non-alcoholic fatty liver disease

Assessments of liver biopsies are important in the diagnosis and management of non-alcoholic fatty liver disease. Histology remains the 'gold standard' for making the important distinction between simple steatosis, which is generally non-progressive and readily reversible, and steatohepatitis, which has the potential to progress to severe fibrosis or cirrhosis. Liver biopsy may also identify other causes of liver disease in patients thought to have fatty liver disease and vice versa. Histological grading and staging of fatty liver disease require further study but these are potentially important approaches for studying disease severity and progression, particularly in the context of clinical trials to assess novel therapeutic approaches.     

Serum retinol-binding protein 4 levels are elevated in non-alcoholic fatty liver disease

Objective Retinol‐binding protein 4 (RBP4) is a recently identified adipokine that is elevated in the serum in several insulin‐resistant states. We investigated the relationship between non‐alcoholic fatty liver disease (NAFLD) and serum RBP4 in nondiabetic adults. Methods One hundred and fifty‐nine nondiabetic, non‐alcoholic subjects (95 males and 64 females) participated in this study. Division of subjects into a NAFLD group (n = 73; 45 males and 28 females) or a normal group (n = 86; 50 males and 36 females) was based on the presence of fatty liver disease determined by sonography. Results Serum RBP4 levels in the NAFLD group were significantly higher than those in the normal group (62·8 ± 16·0 mg/l vs. 51·7 ± 14·6 mg/l, P < 0·0001). Multiple logistic regression analysis revealed that the RBP4 level was an independent factor associated with NAFLD (P = 0·0042). In addition, serum RBP4 levels were positively correlated with serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ‐glutamyltranspeptidase (GGT) levels. The significant association between serum RBP4 and GGT levels remained even after adjusting for age, gender, body mass index, the homeostasis model of assessment (HOMA) value and the presence of NAFLD (r = 0·3097, P = 0·0002). Conclusion Serum RBP4 levels are significantly associated with NAFLD and liver enzymes.     

Chemerin,retinol binding protein-4, cytokeratin-18 and transgelin-2 presence in sera of patients with non-alcoholic liver fatty disease

Background. Chemerin and retinol binding protein-4 (RBP-4) are adipokines which may play a role in the progression of NAFLD. It has been also suggested that cytokeratin-18 (CK-18) could be a marker of hepatocyte caspase-directed death while transgelin-2 production could reflect stage of liver fibrosis. The aim of this study was to evaluate the level of the above adipokines in sera of patients with NAFLD and determine the relation between the level of transgelin-2 and fibrosis-4 index (FIB-4).Material and methods. Ninety-five subjects included initially to the study were divided into four groups: (I) prediabetics, obese with NAFLD and metabolic syndrome (Ms), (II) lean with NAFLD and without MS, (III) obese without NAFLD and MS, and (IV) healthy individuals. We determined the levels of chemerin, RBP-4, transgelin-2 and CK-18 fragments in sera of patients with NAFLD. Moreover, we examined if the levels of CK-18 fragments and transgelin-2 correlates with FIB4 value. Results. Chemerin and RBP-4 were highly expressed in sera of all NAFLD, especially in obese individuals. Chemerin level was also linked to MS. High level of serum CK-18 fragments and transgelin-2 did not correlate with obesity and MS, but seemed to correlate with progression of NAFLD to liver fibrosis.Conclusions. In conclusion, the production of the two adipokines, chemerin and RBP-4, is strongly associated with obesity in patients with NAFLD. Serum concentrations of CK-18 fragments and transgelin-2 correlate with the severity of NAFLD, but not with obesity.