脂肪细胞型脂肪酸结合蛋白（A-FABP）在脑缺血性中风中的作用机制研究

Cerebral ischemic stroke is one of the major causes of death and permanent disability in China. Obesity is associated with risk factors such as hypertension, hypercholesterolemia and diabetes that increase stroke incidence. Adipocyte fatty acid binding protein (A-FABP) is an adipokine that links obesity to its related complications including steatohepatitis and atherosclerosis through its pro-inflammatory activity. A-FABP is mainly expressed in adipocytes and macrophages and its circulating level is increased in obese patients. Clinical evidence suggests that A-FABP is implicated in the pathogenesis of ischemic stroke but the underlying mechanism remains elusive..Our preliminary data showed that circulating A-FABP is independently associated with ischemic stroke. Animal study demonstrated that serum A-FABP and its expression in brain were markedly elevated in mice after experimental stroke. A-FABP deficiency significantly alleviated stroke-induced neurological deficits and infarct size which were accompanied by reduced inflammation, oxidative stress and apoptosis in brain. Blood brain barrier (BBB) disruption was also attenuated associating with decreased matrix metalloproteinases (MMPs) expression. Consistently, pre-treatment of A-FABP inhibitor markedly diminished stroke-induced brain injury in mice. .Recent study showed that MMP9 modulates BBB permeability by degrading tight junction proteins and its expression can be induced by elevated oxidative stress and inflammation. Since our previous study showed that A-FABP mediates macrophage inflammation response by forming a positive feedback loop with JNK/ AP-1 inflammatory signaling pathway while A-FABP deficiency attenuates stroke-induced oxidative stress. We therefore hypothesize that A-FABP alters BBB permeability through instigating oxidative stress and inflammation contributing to the exacerbation of brain damage after ischemic stroke. .The results of this study allow a better understanding on the pathological pathway that link obesity to ischemic stroke and to evaluate if A-FABP inhibitor is a potential therapeutic drug for the prevention or improvement of functional outcome after stroke.

缺血性脑中风已经成为我国城市和农村人口的第一致残和死亡的原因，且发病有逐年增多的趋势。大量证据表明肥胖会导致 II 型糖尿病，高血压以及高胆固醇等疾病从而增加脑中风的风险。脂肪细胞型脂肪酸结合蛋白（A-FABP)是一种由脂肪组织和巨噬细胞分泌的细胞因子，广泛参与肥胖相关的炎性代谢性疾病。本课题组在国际上首次发现A-FABP 可分泌入血，其血清水平在肥胖患者中显著增加。我们的前期临床研究发现缺血性脑中风病人血清 A-FABP水平显著升高，并且与脑缺血中风后的结果和死亡率呈正相关。血清A-FABP水平亦与脑缺性中风的诱导因素心机动脉硬化相关。然而A-FABP在肥胖相关的脑缺性中风中的作用还有待研究。本课题旨在探讨A-FABP在肥胖相关的脑缺性中的病理作用及分子机理，并评价A-FABP抑制剂是否是预防或改善中风后功能结果的潜在治疗药物, 研究结果将为脑缺血性中风的预防和治疗提供新的靶点。

缺血性脑中风已经成为我国城市和农村人口的第一致残和死亡的原因，且发病有逐年增多的趋势。大量证据表明肥胖会导致 II 型糖尿病，高血压以及高胆固醇等疾病从而增加脑中风的风险。脂肪细胞型脂肪酸结合蛋白（A-FABP)是一种由脂肪组织和巨噬细胞分泌的细胞因子，广泛参与肥胖相关的炎性代谢性疾病。本课题组在国际上首次发现A-FABP 可分泌入血，其血清水平在肥胖患者中显著增加。我们的前期临床研究发现缺血性脑中风病人血清 A-FABP水平显著升高，并且与脑缺血中风后的结果和死亡率呈正相关。血清A-FABP水平亦与脑缺性中风的诱导因素心机动脉硬化相关。然而A-FABP在肥胖相关的脑缺性中风中的作用还有待研究。本课题旨在探讨A-FABP在肥胖相关的脑缺性中的病理作用及分子机理，并评价A-FABP抑制剂是否是预防或改善中风后功能结果的潜在治疗药物, 研究结果将为脑缺血性中风的预防和治疗提供新的靶点。在本课题中，我们发现缺血性脑中风能够提高巨噬细胞和星形胶质细胞中A-FABP的表达，A-FABP过表达激活下游JNK/c-Jun通路，从而引起金属基质蛋白酶9的转录和表达。MMP-9进一步降解血脑屏障中的紧密连接蛋白，从而造成血脑屏障的破坏，进一步引起炎症细胞和细胞因子的浸润脑组织造成脑损伤。同时，我们研究发现，不论是基因敲除还是药物抑制A-FABP，均能明显的改善小鼠缺血性脑中风造成的脑损伤，证实了A-FABP在调控缺血性脑损伤中起到的有害作用。我们同时在临床实验中，也证实了这一结论。我们发现了缺血性脑中风患者血液A-FABP水平与MMP-9水平均显著性升高，且呈正相关趋势。A-FABP血液水平与缺血性脑中风患者的脑损伤大小呈正相关趋势。因此，我们从多角度，采用多种手段，证实了A-FABP通过JNK/c-Jun通路调控MMP-9的产生进而调控血脑屏障的破坏从而加重了缺血性脑损伤的作用。因此，我们的成果证实A-FABP在缺血性脑中风后调控脑损伤的负面作用，阐明了A-FABP可作为缺血性脑中风的新治疗靶点。