Pharmacological inhibition of adipocyte fatty acid binding protein alleviates both acute liver injury and non-alcoholic steatohepatitis in mice
Pharmacological inhibition of adipocyte fatty acid binding protein alleviates both acute liver injury and non-alcoholic steatohepatitis in mice
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DOI：
10.1016/j.jhep.2012.10.022
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发表时间：
2013-02-01
影响因子：
25.7
通讯作者：
Lam, Karen S. L.
中科院分区：
文献类型：
--
作者：
Hoo, Ruby L. C.;Lee, Ida P. C.;Lam, Karen S. L.
背景与目的：脂肪细胞脂肪酸结合蛋白（A-FABP）是巨噬细胞炎症反应的关键介质。在非酒精性脂肪性肝病（NAFLD）患者中观察到A-FABP的肝脏表达和循环水平增加。在这里，我们研究了A-FABP在脂多糖（LPS）诱导的急性肝损伤和高脂高胆固醇（HFHC）饮食诱导的小鼠NAFLD.Methods的作用：小鼠与LPS诱导的急性肝损伤和HFHC饮食诱导的肥胖症治疗与A-FABP抑制剂BMS 309403。结果：与健康对照组相比，LPS诱导的急性肝损伤小鼠和HFHC饮食诱导的肥胖小鼠的枯否细胞中A-FABP的表达显著升高。用BMS 309403预处理小鼠导致LPS诱导的丙氨酸转氨酶血清水平升高和促炎细胞因子的肝脏产生减少。同样，用BMS 309403长期治疗HFHC饮食诱导的肥胖小鼠改善了肝脂肪变性、巨噬细胞浸润和肝细胞的细胞气球样变。肝功能和形态学的这种改善伴随着c-Jun和NF-κ B活化的显著降低。用BMS 309403预处理抑制LPS和棕榈酸酯诱导的大鼠枯否细胞的促炎反应。腺病毒介导的异位表达A-FABP单独是足以诱导肝损伤和炎症mice.Conclusions：这些研究结果表明，A-FABP是一个重要的贡献者，LPS诱导的急性肝损伤和饮食诱导的NAFLD通过增强库普弗细胞的炎症。A-FABP的药理学抑制可能是治疗肥胖相关非酒精性脂肪性肝炎的一种有前景的方式。(C)2012年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Adipocyte fatty acid binding protein (A-FABP) is a key mediator of inflammatory response in macrophages. Increased hepatic expression and circulating levels of A-FABP have been observed in patients with non-alcoholic fatty liver disease (NAFLD). Here, we investigated the role of A-FABP in both lipopolysaccaride (LPS)-induced acute liver injury and high fat high cholesterol (HFHC) diet-induced NAFLD in mice.Methods: Mice with LPS-induced acute liver injury and HFHC diet-induced obesity were treated with the A-FABP inhibitor BMS309403. Liver tissues of the mice were analyzed by immunohistochemistry, Western blot or real-time PCR.Results: A-FABP expression in Kupffer cells was significantly elevated in mice with LPS-induced acute liver injury and HFHC diet-induced obesity, as compared to their healthy controls. Pretreatment of mice with BMS309403 led to a diminished LPS-induced elevation in serum levels of alanine transaminase and hepatic production of pro-inflammatory cytokines. Likewise, chronic treatment of HFHC diet-induced obese mice with BMS309403 ameliorated hepatic steatosis, macrophage infiltration, and cellular ballooning of hepatocytes. Such improvements in liver function and morphology were accompanied by significantly decreased activation of both c-Jun and NF-kappa B. Pretreatment with BMS309403 suppressed both LPS- and palmitate-induced pro-inflammatory responses in isolated rat Kupffer cells. Adenovirus-mediated ectopic expression of A-FABP alone was sufficient to induce liver injury and inflammation in mice.Conclusions: These findings suggest that A-FABP is an important contributor to both LPS-induced acute liver injury and diet-induced NAFLD by potentiating inflammation in Kupffer cells. Pharmacological inhibition of A-FABP may represent a promising modality for obesity-related non-alcoholic steatohepatitis. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.