瘦素与肝纤维化

瘦素（leptin）是1994年首次通过定向克隆技术成功克隆的一种代谢性激素,由肥胖（OB）基因编码,人OB基因位于7号染色体的长臂（7q31．3）,由3个外显子和2个内含子构成。瘦素是一种分泌蛋白,由167个氨基酸组成,相对分子质量为16000。瘦素必须与相应受体（ob—R）结合才能发挥作用。目前发现ob-R有a、b、c、d、e和f6种亚型,其中ob-Rb为长型受体,也是功能性受体,ob—Re是可溶性受体,与循环中的瘦素形成复合物,通过调节游离与结合的瘦素比例可改变其生物学活性,其余为短型受体叫。     

瘦素与肝纤维化

瘦素(leptin)是由ob基因(位于人类染色体7q31.3)编码的一种肽类激素,通过多种形式的瘦素受体(obese gene receptor,OB-R),作用于中枢和外周的多个位点,影响机体许多生理系统及代谢通路.自1998年Potter发现活化的肝星状细胞表达瘦素后,人们开始关注瘦素与肝脏疾病的关系.近年研究发现,瘦素与肝纤维化的发生有密切关系,而且与肝纤维化分级相关[1～5].     

瘦素与肝纤维化

瘦素是肥胖基因的编码产物,主要由脂肪组织分泌,与摄食行为和能量代谢的调节密切相关。近来发现瘦素不单纯是抗肥胖激素,而是涉及多系统的多功能细胞因子,它对肝病的作用愈来愈受到关注。肝纤维化是肝脏对各种慢性损伤的一种修复应答反应,其持续发展将演变为肝硬化,有关肝纤维化的研究对预防肝硬化、控制慢性肝病有重要意义。本文就瘦素对肝纤维化作用的最新研究进展进行综述。     

瘦素与肝纤维化

瘦素是肥胖基因(ob基因)的编码产物,通过与其受体结合在体内发挥多种生物学作用,调节摄食、能量代谢、生殖、造血、免疫等生理功能.参与炎性反应、损伤修复等病理生理过程.肝纤维化是多种原因所致慢性肝损伤的修复反应,是各种慢性肝病共同的病理基础.研究发现瘦素与肝纤维化的发生发展有一定的关系,本文就此作一综述.     

瘦素与肝纤维化

1994年Zhang等人通过定向克隆技术首次发现了ob基因和该基因编码的蛋白产物—瘦素,瘦素的发现给肥胖及能量代谢领域带来了一次重大突破。瘦素不仅仅只对能量代谢起作用,它在病理生理学上的影响涉及许多系统。     

瘦素与肝纤维化

瘦素(Leptin)是由ob基因(位于人类染色体7q32)编码的一种167个氨基酸组成的分泌型蛋白质，分子量约为14～16kD，它主要由白色脂肪组织产生，进入血循环后，游离或与瘦素结合蛋白结合，通过多种组织及多种形式的瘦素受体，作用于包括中枢和外周的多个位点，影响机体许多生理系统及代谢通路，具有广泛的生物学效应。最新的一些临床与研究显示，Leptin与肝纤维     

瘦素与肝纤维化关系及研究方法

瘦素与肝纤维化关系密切.本文结合既往的动物实验以及作者对肝组织原位瘦素的研究, 推测肝脏原位瘦素的出现可能意味着肝纤维化进程启动的一个重要步骤,并对瘦素研究方法进行分析.     

瘦素与肝纤维化关系的研究进展

瘦素 (leptin)是由ob基因 (位于人类染色体 7q3 2 )编码的一种 167个氨基酸组成的分泌型蛋白质 ,相对分子质量约为 14～16× 10 3 ,它主要由白色脂肪组织产生 ,进入血循环后 ,游离或与瘦素结合蛋白结合 ,通过多种组织及多种形式的瘦素受体 ,作用于包括中枢和外周的多个位点 ,影响机体许多生理系统及代谢通路 ,具有广泛的生物学效应。最新的一些临床与研究显示 ,瘦素与肝纤维化具有密切的关系。作为新的肝纤维化形成因子 ,其机制研究已越来越引起人们的关注[1,2 ] 。但是瘦素在肝纤维化中到底起到什么样的作用 ,学术界还是有较大的争论。一、…     

瘦素与酒精性肝病肝纤维化的关系

研究瘦素与酒精性肝病 (ALD)肝纤维化发生发展的关系。用ELISA法检测 6 0例ALD患者血清瘦素水平 ,16例健康人作为对照组 ,同步检测了ALD患者的血清肝纤维化指标HA、LN、PC -Ⅲ及TGFβ1,对血清瘦素与肝纤维化指标、肝组织纤维化分期间的关系进行了分析。ALD患者的血清瘦素水平明显高于对照组 ,在单纯性脂肪肝 (AFL)、脂肪性肝炎 (AH)、脂肪性肝硬化 (ALC)瘦素水平依次增高 ,差异有显著性。在AH、ALC血清瘦素水平与肝纤维化血清学指标和TGFβ1正相关 ,ALD患者的血清瘦素水平与肝组织纤维化分期密切相关。血清瘦素是ALD患者肝纤维化的始动因子之一     

Leptin administration exacerbates thioacetamide-induced liver fibrosis in mice

AIM: To investigate the effects of leptin administration on liver fibrosis induced by thioacetamide (TAA). METHODS: Twenty-four male C57Bl/6 mice were randomly allocated into four groups, which were intra-peritoneally given saline (2 mL/kg), leptin (1 mg/kg), TAA (200 mg/kg), TAA (200 mg/kg) plus leptin (1 mg/kg) respectively, thrice a week. All mice were killed after 4 wk. The changes in biochemical markers, such as the levels of alanine aminot-ransferase (ALT) and aspartate aminotransferase (AST) in serum and superoxide dismutase (SOD), malondialdehyde (MDA) in liver were determined. For histological analysis, liver tissues were fixed with 10% buffered formalin, embedded with paraffin. Hematoxylin-eosin (HE) staining and picric acid-Sirius red dyeing were performed. The level of α1(I) procollagen mRNA in liver tissues was analyzed by RT-PCR. RESULTS: Apparent liver fibrosis was found in TAA group and TAA plus leptin group. Compared to saline group, the levels of ALT and AST in serum and MDA in liver increased in TAA group (205.67±27.69 U/L vs50.67±10.46 U/L, 177.50±23.65 U/L vs 76.33±12.27 U/L, 2.60±0.18 nmol/mg pro vs 1.91±0.14 nmol/mg pro, P<0.01) and in TAA plus leptin group (256.17±22.50 U/L vs 50.67±10.46 U/L, 234.17±27.37 U/L vs 76.33±12.27 U/L, 2.97±0.19 nmol/mg pro vs 1.91±0.14 nmol/mg pro,P<0.01). The level of SOD in livers decreased (51.80±8.36 U/mg pro vs 81.52±11.40 U/mg pro, 35.78±6.11 U/mg pro vs 81.52± 11.40 U/mg pro, P<0.01) and the level of α1(I) procollagen mRNA in liver tissues also increased (0.28±0.04 vs 0.11± 0.02, 0.54±0.07 vs 0.11±0.02, P<0.01). But no significant changes were found in leptin group and saline group. Compared to TAA group, ALT, AST, MDA, and α1(I) procollagen mRNA and grade of liver fibrosis in TAA plus leptin group increased (256.17±22.50 U/L vs 205.67± 27.69 U/L, P<0.05; 234.17±27.37 U/L vs 177.50±23.65 U/L, P<0.05; 2.97±0.19 nmol/mg pro vs 2.60±0.18 nmol/mg pro,P<0.05; 0.54±0.07 vs 0.28±0.04, P<0.01; 3.17 vs 2.00, P<0.05), and the level of SOD in liver decreased (35.78±6.11 U/mg pro vs 51.80±8.36 U/mg pro, P<0.05). There were similar changes in the degree of type I collagen deposition confirmed by picric acid-Sirius red dyeing. CONCLUSION: Leptin can exacerbate the degree of TAA-induced liver fibrosis in mice. Leptin may be an important factor in the development of liver fibrosis.     

Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease

BACKGROUND/AIMS: Data from animal models of fibrosis and fatty liver suggest that leptin may mediate the profibrogenic responses in the liver, but the association of leptin and liver fibrosis in human nonalcoholic fatty liver disease (NAFLD) remains undefined. We aimed at determining the relation between leptin and liver fibrosis in human NAFLD. METHODS: Human plasma leptin and several indicators of insulin resistance were measured in 88 NAFLD patients and matched controls. RESULTS: Leptin levels were significantly greater in patients with more advanced fibrosis (P = 0.005). By multivariate analysis, the significant association between leptin and fibrosis was abolished (adjusted P = 0.3) when controlling for confounders including age, gender, BMI, diabetes and insulin resistance. Only age (adjusted P = 0.006) and insulin sensitivity (adjusted P = 0.04) correlated significantly with fibrosis stage. A second liver biopsy was performed in 39 out of the 88 patients at 27.9 +/- 16 months. Leptin levels were not significantly different between patients who had fibrosis progression (n = 10) and those who did not (n = 29). CONCLUSIONS: In human NAFLD, no relationship between leptin levels and fibrosis stage was demonstrated. The correlation of leptin and fibrosis severity seems to be an indicator of the factors that determine leptin production.     

Leptin, free leptin index, insulin resistance and liver fibrosis in children with non-alcoholic fatty liver disease

OBJECTIVE: Prevalence of non-alcoholic fatty liver disease (NAFLD) among children is increasing dramatically. It is unclear why some patients develop steatohepatitis (NASH), fibrosis and cirrhosis from steatosis, and others do not. A role for leptin has been claimed. This study aims to evaluate the relationship between leptin, insulin resistance (IR) and NAFLD in children. DESIGN AND METHODS: In 72 biopsy-proven NAFLD children (aged 9-18 years; 51M/21F), fasting leptin and its soluble receptor (sOB-R) were measured; free leptin index (FLI) was calculated as leptin/sOB-R; IR was estimated by homeostasis model assessment (HOMA-IR) and insulin sensitivity index (ISI-comp); glucose tolerance by oral glucose tolerance test (OGTT). Percentage of total body fat (TBF) by dual-energy X-ray absorptiometry (DXA) was available in 65 patients. RESULTS: Prevalence of diabetes, impaired fasting and/or after load glucose tolerance was 11%. HOMA-IR and ISI-comp values were 2.55 +/- 1.39 and 4.4 +/- 2. NASH was diagnosed in 38 and simple steatosis in 25 children; diagnosis was indeterminate in 29 children. Increased fibrosis, mostly of mild severity, was observed in 41 patients. Median NAFLD activity (NAS) score was 3.42 +/- 1.60. According to histology, levels of leptin and FLI increased as steatosis (leptin from 11.9 +/- 6.3 in score 1 to 17.4 +/- 6.9 in score 2 (P = 0.01) and 22.2 +/- 6.8 ng/ml in score 3 (P < 0.001); FLI 2.56 +/- 1.40, 3.57 +/- 0.34, 4.45 +/- 0.64 respectively (P = 0.05)); ballooning (from 13.7 +/- 6.7 in score 1 to 17 +/- 7.5 in score 2 (P = 0.001) and 22.1 +/- 7.1 ng/ml in score 3 (P = 0.01); FLI 2.81 +/- 1.50, 3.40 +/- 1.65, 4.57 +/- 1.67 (P = 0.01 between 0 and 2)); fibrosis (from 14.3 +/- 7 to18.3 +/- 6.9; P = 0.03; FLI 3.03 +/- 1.57 vs 3.92 +/- 077; P < 0.05) and NAS score (score 1-2: 12.9 +/- 6.9; score 3-4: 17 +/- 6.9 (P = 0.01); score 5-7: 22.9 +/- 7.5 ng/ml (P = 0.03); FLI 2.70 +/- 1.53, 3.12 +/- 1.53, 4.58 +/- 1.57 P = 0.01 and P = 0.05 between 1-2 vs 3-4 and 3-4 vs 5-7 respectively) worsened. Higher leptin correlated with more severe steatosis, ballooning and NAS score (r(0) = 0.6, 0.4 and 0.6 respectively; for all P < 0.001); FLI with ballooning (r(0) = 0.4, P < 0.0001), steatosis (r(0) = 0.5, P < 0.0001) and NAS score (r(0) = 0.5, P < 0.0001). CONCLUSIONS: Leptin and liver injury correlated independently of age, BMI and gender in the present study. Nevertheless, any causative role of leptin in NAFLD progression could be established. Thus, studies are needed to define whether the hormone plays a major role in the disease.     

瘦素与脂肪性肝病

脂肪性肝病(fatty liver disease，FLD)是遗传一环境一代谢应激相关因素所致的以肝细胞脂肪变性为主的临床病理综合征。FLD包括由酒精所致的酒精性肝病(alcoholic liver disease，ALD)和肥胖、高脂等代谢紊乱所致的非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)。在病理上分为单纯性脂肪肝、脂肪性肝炎、脂肪性肝纤维化和脂肪性肝硬化。在FLD的发生发展过程中，瘦素的作用日益受到重视。     

砷与肝纤维化

长期砷暴露引起的肝损伤,可进展为肝纤维化、肝硬化.对砷暴露人体和动物的肝组织病理研究发现,肝细胞呈广泛脂肪变性、坏死及汇管区炎性细胞浸润及纤维化.目前,砷致肝纤维化发生机制的研究尚少有报道,且迄今没有合适的动物模型.本文综述了砷与肝纤维化相关性及有关机制的研究进展.     

基因多态性与肝纤维化

无论病因如何,肝损伤后的自然发展史存在显著的个体差别.HBV感染患者也可出现自然转阴、持续无症状携带状态、慢性化或恶变的不同转归[1].患者的临床转归除可能受病毒载量,病毒基因型、生活方式和环境因素影响外,宿主的遗传背景和基因多态性可能也在机体对病毒感染后的免疫反应、肝损伤和纤维化发生、向终末期肝硬化和肝癌的发展和转归中起到重要作用[2].