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Role of adipocytokine in progression and therapeutic resistance in chronic liver diseases and hepatocellular carcinoma

脂肪细胞因子在慢性肝病和肝细胞癌进展和治疗抵抗中的作用

基本信息

批准号：
16590633
负责人：
IKEJIMA Kenichi
金额：
$ 2.11万
依托单位：
Juntendo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

In the present study, we investigated the role of adipocytokine in progression and therapeutic responses in chronic liver diseases including non-alcoholic steatohepatitis (NASH) and chronic hepatitis C. To evaluate the role of metabolic factors in progression of steatohepatitis, we utilized KK-Ay mice, which resemble human metabolic syndrome. KK-Ay mice developed more severe steatohepatitis and subsequent hepatic fibrosis as compared to C57B1/6 controls when they were fed a diet lacking methionine and choline (MCD diet). KK-Ay mice not only showed extremely low serum adiponectin levels at basal condition, but also failed to increase serum adiponectin levels following dietary treatment, suggesting that adiponectin plays a key role in prevention of progressive steatohepatitis. On the other hand, we also evaluated whether adipocytokines affect anti-viral effect of interferon in vitro. Leptin blunted anti-viral effect of IFN-a through inhibition of both phosphorylation of STAT-1 and subsequent induction of 2'-5' oligoadenylate synthase (OAS) activity. Moreover, we demonstrated that hepatic steatosis is a predictor of poor sustained viral response (SVR) in interferon and ribavirin combination therapy for chronoc hepatitis C, supporting the hypothesis that host-related metabolic factors modulate therapeutic efficacy of anti-viral therapy in patients with chronic hepatitic C. Collectively, expression pattern of adipocytokines regulates progression and therapeutic responses in metabolic syndrome-related fatty liver diseases and chronic hepatitis C.

在本研究中，我们研究了脂肪细胞因子在慢性肝病（包括非酒精性脂肪性肝炎（NASH）和慢性丙型肝炎）的进展和治疗反应中的作用。为了评估代谢因素在脂肪性肝炎进展中的作用，我们使用了类似于人类代谢综合征的KK-Ay小鼠。与C57 B1/6对照组相比，KK-Ay小鼠在喂食缺乏蛋氨酸和胆碱的饲料（MCD饲料）时发生了更严重的脂肪性肝炎和随后的肝纤维化。KK-Ay小鼠不仅在基础条件下表现出极低的血清脂联素水平，而且在饮食治疗后也未能增加血清脂联素水平，这表明脂联素在预防进行性脂肪性肝炎中起关键作用。另一方面，我们还在体外研究了脂肪细胞因子是否影响干扰素的抗病毒作用。瘦素通过抑制STAT-1的磷酸化和随后诱导2 '-5'寡腺苷酸合酶（OAS）活性来减弱IFN-α的抗病毒作用。此外，我们证明了肝脂肪变性是干扰素和利巴韦林联合治疗慢性丙型肝炎的持续病毒应答（SVR）较差的预测因子，支持宿主相关代谢因素调节慢性丙型肝炎患者抗病毒治疗疗效的假设。总体而言，脂肪细胞因子的表达模式调节代谢综合征相关脂肪肝疾病和慢性丙型肝炎的进展和治疗反应。