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.     

日本血吸虫病小鼠肝纤维化过程中VI型胶原的表达变化

目的:阐明血吸虫病肝纤维化时肝脏Ⅵ型前胶原m RNA表达和胶原含量的变化。方法:采用Northern核酸分子杂交和免疫组化技术。结果:小鼠感染后8 wk 时,肝内α1(Ⅵ)前胶原m RNA的表达量显著增加,10 w k时,其表达值达高峰,12～16 w k,略有下降,但直至20 wk 仍维持在较高水平。免疫组化染色显示,肝内Ⅵ型胶原在感染后8 wk 时出现于中央静脉周围和肝窦壁,10 w k 时,在肝组织内继续增多,12 w k 时虫卵肉芽肿内明显着色,16 w k 时,其含量达高峰,20 wk 时,广泛分布于汇管区、虫卵肉芽肿内及其周围,并形成致密的网络间隔。结论:血吸虫病肝纤维化形成过程中肝脏α1(Ⅵ)前胶原m RNA 表达和胶原含量均有显著增加,表明Ⅵ型胶原的检测对血吸虫病肝纤维化的评估可能有重要价值     

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.     

瘦素在肝纤维化中的作用及机制研究进展

瘦素(leptin)是由肥胖基因编码的、具有多种功能的多肽类激素,目前关于瘦素在慢性肝病中的作用研究较多,此文就瘦素与肝非实质细胞、细胞因子的关系及在肝纤维化发展机制中的作用研究进展作一综述。     

肝纤维化血清学标志对慢性肝病的诊断价值

目的：通过对肝硬化等慢性肝病者血清中透明质酸、Ⅲ型前胶原含量的检测，探讨肝纤维化血清学标准对慢性肝病的诊断价值。方法：以健康对照组和其他胃肠疾病组为对照，放射免疫分析法测定血清中ＨＡ、ｐｃⅢ含量，并将各组结果进行统计学分析，比较。结果：肝硬化代偿、失代偿期两组血清ＨＡ、ｐｃⅢ含量均显著高于健康对照组与胃肠病且。肝硬化组中，Ｃｈｉｌｄ－Ｐｕｇｈ‘ｓＡ．Ｂ．Ｃ三组及其积分与血清ＨＡ．ｐｃⅢ含量之间均有     

慢性乙型肝炎患者血清瘦素水平与肝纤维化程度相关

目的研究血清瘦素与慢性乙型肝炎肝脏炎症和肝纤维化程度之间的关系.方法20例慢性乙型肝炎患者在聚乙二醇α-2a干扰素治疗前及治疗48周、随访24周后进行肝穿刺病理学检查,另20例患者进行1次肝穿刺.采用ELISA方法检测40例慢性乙型肝炎患者血清瘦素水平,20名健康人作为对照组,对血清瘦素与肝组织炎症分级、纤维化分期间的关系进行分析.结果慢性乙型肝炎患者血清瘦素水平(12.89±7.47)ng/ml明显高于健康对照组(2.57±1.29)ng/ml,差异有统计学意义(P＜0.05).S0(5例)、S1(14例)、S2(16例)、S3(14例)、S4(11例)期肝纤维化血清瘦素水平分别为(2.62±0.89)ng/ml、(5.26±1.60)ng/ml、(13.15±4.52)ng/ml、(17.08±3.78)ng/ml、(21.56±5.89)ng/ml,随纤维化程度加重,血清瘦素水平增加;血清瘦素水平与肝组织纤维化分期成正相关(r=0.845,P＜0.01).20例患者在聚乙二醇α-2a干扰素治疗前、后肝组织纤维化计分分别为10.91±6.32和7.43±4.15,差异有统计学意义(P＜0.05);治疗前、后血清瘦素水平分别为18.35±4.93和13.57±5.39,差异有统计学意义(P=0.006).G0(4例)、G1(12例)、G2(22例)、G3(16例)、G4(6例)级炎症血清瘦素水平分别为(2.66±1.03)ng/ml、(9.04±4.92)ng/ml、(13.22±7.38)ng/ml、(16.19±7.71)ng/ml、(17.41±4.25)ng/ml,G0与G1级、G1与G2级患者血清瘦素水平差异无统计学意义(P=0.006),G2、G3、G4级患者血清瘦素水平差异无统计学意义(P＞0.05),G3～G4级患者血清瘦素水平与G1级相比,差异有统计学意义(P＜0.05).结论血清瘦素与慢性乙型肝炎肝组织纤维化分期密切相关.     

Effect of Astragalus complanatus fiavonoid on anti-liver fibrosis in rats

AIM: To observe the anti-liver fibrosis effect of Astragalus complanatus fiavonoids (ACF) in rats.METHODS: The liver fibrosis model in rats was established by injecting interperitoneally 0.2 mL/100 g 0.5% dimethylnitrosamine, thrice a week. Meanwhile, the rats were administered ACF (30, 60, 120 mg/kg) or colchicine (0.1 mg/kg) once a day for 1 mo. Serum N-propeptide of type I procollagen (PINP) and type Ⅲ procollagen (PⅢNP) was measured using ELISA. Malondialdehyde (MDA) and superoxide dismutase (SOD) in hepatic tissue were evaluated. Matrix metal protease-1 (MMP-1) mRNA expression was assayed by RT-PCR and the protein expression of tissue inhibitor of metal protease-1 (TIMP-1) was analyzed by immunohistochemistry.RESULTS: In the ACF groups, SOD activity increased and MDA content decreased in comparison to the liver fibrosis model group. The serum PINP and PⅢNP contents in ACF-2 and -3 group decreased compared to those in model group.In ACF-2 and -3 group, the expression of MMP-1 mRNA increased significantly and the protein expression of TIMP-1 decreased compared to that in model group.CONCLUSION: The antifibrotic mechanisms of ACF are associated with its influence on lipid peroxidation and collagen synthesis and degradation.     

Interferon-gamma exacerbates liver damage, the hepatic progenitor cell response and fibrosis in a mouse model of chronic liver injury

BACKGROUND/AIMS: Several previous studies have suggested that interferon gamma (IFNgamma) may play a key role during hepatic progenitor cell (HPC) mediated liver regeneration. However to date, no studies have directly tested the ability of IFNgamma to mediate the HPC response in an in vivo model. METHODS/RESULTS: Administration of IFNgamma to mice receiving a choline deficient, ethionine (CDE) supplemented diet to induce chronic injury resulted in an augmented HPC response. This was accompanied by increased inflammation, altered cytokine expression and hepatic fibrosis. Serum alanine aminotransferase activity, hepatocyte apoptosis and Bak staining were significantly increased in IFNgamma-treated, CDE-fed mice, demonstrating that liver damage was exacerbated in these animals. Administration of IFNgamma to control diet fed mice did not induce liver damage, however it did stimulate hepatic inflammation. CONCLUSIONS: Our results suggest that IFNgamma increases the HPC response to injury by stimulating hepatic inflammation and aggravating liver damage. This is accompanied by an increase in hepatic fibrogenesis, supporting previous reports which suggest that the HPC response may drive fibrogenesis during chronic liver injury.     

血吸虫病肝纤维化过程中肝脏前胶原mRNA的表达变化研究

目的阐明血吸虫病肝纤维化过程中,肝脏前胶原基因表达的动态变化规律。方法应用Ｎｏｒｔｈｅｒｎ核酸分子杂交技术,检测血吸虫感染小鼠在肝纤维化过程中肝脏前胶原ｍＲＮＡ表达量的变化。结果小鼠感染血吸虫后６周时,肝内α１（Ⅰ）和α１（Ⅲ）前胶原ｍＲＮＡ的表达量即有显著增加,８周时,α１（Ⅰ）前胶原ｍＲＮＡ的表达量已达高峰,α１（Ⅲ）和α１（Ⅵ）前胶原ｍＲＮＡ的表达高峰在１０周时出现。１２～１６周时,三者的表达量略有下降,２０周时均又回升。在整个肝纤维化过程中,α１（Ⅰ）前胶原ｍＲＮＡ呈优势表达,α１（Ⅲ）前胶原ｍＲＮＡ次之,α１（Ⅵ）前胶原ｍＲＮＡ的表达量较前二者稍低,但其表达水平的增幅最大。结论肝脏前胶原ｍＲＮＡ表达水平的检测能敏感地反映肝纤维化的趋向,α１（Ⅵ）前胶原ｍＲＮＡ的表达在肝纤维化形成中可能起重要作用。     

Repeated infections with Schistosoma mansoni and liver fibrosis in undernourished mice

The mouse model of schistosomal periportal fibrosis (Symmers' "pipestem" fibrosis), that develops in 30-50% of the infected animals, is not reproduced in undernourished mice. Host nutritional status is likely to be a variable that may influence the outcome and progression of infection, since it interferes with the dynamics of connective tissue changes occurring in chronic hepatic schistosomiasis. Re-infections increase the occurrence of periportal liver fibrosis in well-nourished animals, but it is not known how undernourished mice would behave being repeatedly re-infected. So, 21-day-old male albino Swiss mice were individually exposed to 30 cercariae (percutaneous route) of the BH strain of Schistosoma mansoni, 4 weeks after being on a low-protein diet. Control animals were fed on a commercial balanced chow for mice. The nutritional status was evaluated by body weight gain and measurement of food intake. Mice were divided into four groups: A1 (undernourished, single infected), A2 (well-nourished, single infected), B1 (undernourished, re-infected), B2 (well-nourished, re-infected). The primary infection was performed 4 weeks after ingesting the respective diet. Re-infections started 45 days later, with exposure to 15 cercariae, at 15 day intervals. Mice were sacrificed 18 weeks after the primary exposure. The livers were submitted to morphological (gross and microscopic pathology), morphometric (percentage of fibrosis; granuloma size; volume and numerical densities) by using semi-automatic morphometry, and biochemical (quantification of collagen as hydroxyproline) studies. Worm burdens and hepatic egg counting were also recorded. Values for body weight gains were always lower in undernourished mice, the effects of re-infection being minimal on this regard. Liver and spleen weights were higher in well-nourished mice (either single infected or re-infected) and mainly related to the type of ingested diet. A greater number of re-infected well-nourished mice developed periportal fibrosis, but undernourished re-infected animals did not reproduce this lesion. The percentage of fibrosis and hepatic collagen content were higher in well-nourished mice, but differences between single infected and re-infected groups were not statistically significant.     

肝纤维化的治疗

1.抗肝纤维化治疗某些新的认识:(1)肝星状细胞(HSC) 的活化过程,细胞因子、多肽、细胞外基质(ECM)等均能致HSC的活化。有报道丙型肝炎病毒(HCV)的核心蛋白与HBxAg也有直接激活HSC的作用。Canbay等指出肝细胞的凋亡能诱导HSC的活化,抑制肝细胞凋亡的一个小分子半胱氨酸-天门冬氨酸蛋白酶抑制剂近年已开始临床试用;还可以通过RNA干扰技术阻止肝细胞凋亡而达抗肝纤维化治疗目的。凋     

Soy isoflavone delays the progression of thioacetamide-induced liver fibrosis in rats

Abstract

Objective. Our aim was to investigate the effect of soy isoflavone (SI) on liver fibrosis in a thioacetamide (TAA)-induced rat model. Materials and methods. Twenty-eight rats were assigned to four groups: sham group, fibrosis group, low-dose treatment group (LDg) and high-dose treatment group (HDg). SI (90 or 270 mg/kg) was administered daily during the model development by TAA. Standard liver tests, platelet derived growth factor-BB (PDGF-BB) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured. The expression of collagen, α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) in liver tissue was determined. Electron microscopy was used to perform ultrastructural analysis of the livers. Results. Hepatic fibrosis was induced by 8 weeks of TAA administration. However, following the administration of SI, collagen staining significantly declined as compared with the fibrosis group (p < 0.01). Less collagen fibers around the hepatic stellate cells (HSCs) were observed in HDg as compared to the fibrosis group and LDg. There was no significant difference in standard liver tests between the fibrosis group and the two treatment groups. The levels of PDGF-BB and TIMP-1 in the two SI-treated groups were significantly lower than in the fibrosis group (p < 0.01). The expression of α-SMA and TGF-β1 in HDg was less than that in the fibrosis group and LDg (p < 0.01). Conclusion. Administration of a high dose of SI resulted in an obvious inhibitory effect on liver fibrosis induced by TAA in rats. One hypothesis is that the effect may be related to the inhibition of HSC activation and proliferation.     

肝纤维化的治疗

肝纤维化存在于嗜肝病毒、乙醇、药物、血吸虫、代谢异常以及自身免疫反应等引起的大多数慢性肝病中,是慢性肝病向肝硬化发展的必经病理学过程.有效治疗肝纤维化对于改善慢性肝病预后,降低病死率至关重要.     

IFN-γ对日本血吸虫病肝纤维化小鼠Smads表达的影响

目的 从转录水平探讨参与TGF-β1信号转导的Smads在日本血吸虫感染的BALB/c小鼠形成肝纤维化过程中,以及IFN-γ治疗后的表达情况. 方法 BALB/c小鼠感染日本血吸虫尾蚴后第16周,将其随机分成3组:安慰剂组、吡喹酮治疗组和吡喹酮联合IFN-γ治疗组,治疗8周.分别在感染后第8周、12周、16周和24周,处死小鼠取肝脏组织,一部分进行天狼猩红染色,观察胶原沉积情况;另一部分提取总mRNA,通过RT-PCR检测Smad2.Smad3,Smad4和Smad7 mRNA的表达水平. 结果 肝纤维化模型在感染16周后形成.胶原表达随着感染时间的延长而增加.胶原表达在吡喹酮联合IFN-γ治疗组表达下降,而在安慰剂组和吡喹酮治疗组之间的差别无统计学意义.在肝纤维化形成过程中,Smad3 mRNA在感染16周时增加到正常水平的2倍;Smad2 mRNA的表达水平在感染12周时下降,在16周时,又恢复到正常水平;Smad4和Smad7 mRNA水平变化不明显.在联合治疗后,Smad7 mRNA水平明显增高,Smad2 mRNA保持在低水平上,Smad3 mRNA高于正常对照组,Smad4 mRNA水平仍无明显变化. 结论 Smad3 mRNA表达上调,Smad2 mRNA表达下调以及Smad7 mRNA的低水平表达可能导致小鼠肝纤维化的形成,IFN-γ可能通过诱导Smad7 mRNA表达上调,从而达到抗纤维化的作用.     

库普弗细胞与肝纤维化的关系

活化的库普弗细胞发挥吞噬、抗原提呈、释放细胞因子、免疫调节等功能，成为机体防御的重要屏障，同时也参与了肝脏的炎症损伤、纤维化的形成和降解等病理过程。     

A20在肝纤维化小鼠肝组织中的表达及相关研究

目的研究在肝纤维化小鼠肝组织中A20的表达以及炎性反应激活情况。方法通过喂养C57/B6雄性小鼠含有0.1%的3,5-二乙氧基羰基-1,4-二氢-2,4,6-三甲基吡啶(DDC)饲料,构建肝纤维化模型,分别通过Western印迹、PCR检测肝组织中A20、TGF-β、TNF-α、MCP-1、TLR4的表达情况。结果 DDC饲养小鼠肝纤维化明显,小鼠肝组织中A20表达明显升高,A20 mRNA较对照组升高约4.7倍,差异有统计学意义;DDC组小鼠肝内TGF-β、TNF-α、MCP-1、TLR4 mRNA较对照组均升高,分别升高约2.6倍、12.1倍、91.9倍、3.3倍,差异均有统计学意义。结论 A20在肝纤维化小鼠肝组织中的表达增高,A20在肝纤维化的发生发展过程中具有一定的作用。     

Transplantation of fetal liver epithelial progenitor cells ameliorates experimental liver fibrosis in mice

INTRODUCTION The incidence of hepatic injury and end-stage liver f ibrosis is high in China. Cirrhosis represents a serious health care problem worldwide. The prognosis of patients with the disease is poor, although liver transplantation is a successful t…     

实验性脂肪肝肝纤维化组织中弹性蛋白表达的研究

目的探讨弹性蛋白表达与脂肪肝肝纤维化的关系。方法分别建立高脂饮食、低脂酒精饮食、高脂酒精饮食和四氯化碳大鼠实验性脂肪肝肝纤维化模型,用免疫组织化学方法观察造模肝组织中弹性蛋白的表达。结果低脂饮食组、高脂饮食组和低脂饮食酒精组未见弹性蛋白的表达;高脂饮食酒精组有部分表达,而四氯化碳组均见弹性蛋白的表达;窦周肝细胞表达强度明显高于肝细胞。结论在肝纤维化的发展过程中,弹性蛋白的表达见于肝纤维化后期,与肝纤维化程度相关,可反映肝纤维化的病程;窦周肝细胞（主要是肝星状细胞）在肝纤维化进程中起十分重要的作用。     

胶原沉积抑制因子在肝纤维化中的作用

目的研究乙型肝炎肝组织中胶原沉积抑制因子(decorin)的表达及其与肝纤维化发生的关系。方法用原位杂交法检测55例乙型肝炎患者石蜡包埋肝组织中decorin mRNA的分布和强度。结果decorin mRNA主要分布于肝细胞和纤维细胞胞质。纤维细胞decorin表达阳性率和阳性强度S3期明显高于S0期(P<0.05)。结论decorin在肝纤维化发生发展中具有重要作用;纤维细胞decorin的高表达可成为肝纤维化是否可逆以及肝硬化是否发生的预后指标。     

Prolyl 4-hydroxylase inhibitor (HOE 077) prevents TIMP-1 gene expression in rat liver fibrosis

The effects of a prolyl 4-hydroxylase inhibitor (HOE 077) on tissue inhibitor of metalloproteinase-1 (TIMP-1) and procollagen type I were examined in rat liver fibrosis. HOE 077 (200 ppm) prevented fibrosis by inhibiting the expression of liver type I procollagen and TIMP-1 mRNAs, with liver hydroxyroline content correlated with the reduction in activated stellate cells. HOE 077 prevents fibrosis by inhibiting proline hydroxylation and stellate cell activation, resulting in reduced expression of procollagen and TIMP-1 mRNAs. Received: October 5, 1998/Accepted: December 18, 1998