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Nat Med:武汉大学李红良研究组发表脂肪性肝炎研究成果

摘要 : 2017年2月20日,国际学术权威刊物自然出版集团旗下子刊《Nature Medicine》杂志在线发表了武汉大学人民医院李红良教授研究组的一篇研究论文

2017年2月20日,国际学术权威刊物自然出版集团旗下子刊《Nature Medicine》杂志在线发表了武汉大学人民医院李红良教授研究组的一篇研究论文,研究发现一个调控天然免疫的名为“CFLAR”的分子,可明显改善并逆转非酒精性脂肪肝炎的进程。研究论文题为“Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates”。

目前在世界范围内,非酒精性脂肪性肝炎都缺乏有效治疗药物,这一研究将有助于相关靶向药物的研发。非酒精性脂肪性肝炎多发是当前全球最重要的公共健康问题之一,也是中国发病率最高的慢性肝病类型,目前国内有超过1.5亿该病患者。非酒精性脂肪性肝炎以脂肪在肝脏中过量蓄积为主要特征,肥胖、糖尿病、高脂血症等代谢综合征与该病的发生密切相关。患者可能出现严重的炎症反应及肝细胞损伤,并有较高风险发展成肝纤维化、肝硬化和肝癌。非酒精性脂肪性肝炎严重威胁国人健康。但目前在世界范围内,都对其发病具体机制仍缺乏了解,对应的治疗手段也收效甚微。

李红良教授研究团队长期致力于对心血管和肝脏代谢性疾病的研究。他们经过长达八年的研究证实,一个名为“CFLAR”的分子,是机体天然免疫调控网络中的一员,它在调控细胞内的凋亡信号通路中发挥至关重要的作用。最新研究证实,“CFLAR”分子通过阻断一个名为“ASK1”的酶的激活,可明显抑制非酒精性脂肪性肝炎的炎症发生、肝脏纤维化、胰岛素抵抗和肝脏脂质堆积等一系列疾病过程。在动物身上进行的实验证实,调控“CFLAR”分子后,实验动物已经出现的非酒精性脂肪性肝炎得到明显改善并实现病情逆转。

原文链接:

Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates

原文摘要:

Nonalcoholic steatohepatitis (NASH) is a progressive disease that is often accompanied by metabolic syndrome and poses a high risk of severe liver damage. However, no effective pharmacological treatment is currently available for NASH. Here we report that CASP8 and FADD-like apoptosis regulator (CFLAR) is a key suppressor of steatohepatitis and its metabolic disorders. We provide mechanistic evidence that CFLAR directly targets the kinase MAP3K5 (also known as ASK1) and interrupts its N-terminus-mediated dimerization, thereby blocking signaling involving ASK1 and the kinase MAPK8 (also known as JNK1). Furthermore, we identified a small peptide segment in CFLAR that effectively attenuates the progression of steatohepatitis and metabolic disorders in both mice and monkeys by disrupting the N-terminus-mediated dimerization of ASK1 when the peptide is expressed from an injected adenovirus-associated virus 8–based vector. Taken together, these findings establish CFLAR as a key suppressor of steatohepatitis and indicate that the development of CFLAR-peptide-mimicking drugs and the screening of small-molecular inhibitors that specifically block ASK1 dimerization are new and feasible approaches for NASH treatment.

来源: Nature Medicine 浏览次数:0

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