靶向CFLAR改善小鼠和非人灵长类动物的非酒精性脂肪肝炎

Targeting CASP8 and FADD-Like Apoptosis Regulator Ameliorates Nonalcoholic Steatohepatitis in Mice and Nonhuman Primates

非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)逐渐成为发病率最高的慢性肝病类型。NASH发病常常伴随全身代谢综合征,疾病进展具有发生肝硬化甚至肝癌的高风险。然而,目前临床上尚无一种获批的针对NASH的有效治疗药物。我们的最新研究结果发现,天然免疫重要分子CFLAR[CASP8 and FADD(Fas-associating protein with death domain)-like apoptosis regulator]直在NASH疾病进程中的关键负调控作用。深入的分子机制探索证实,CFLAR接靶向激酶MAP3K5[mitogen-activated protein kinase kinase kinase 5,也称为ASK1(apoptosis signal-regulating kinase 1)]并阻断其N-端二聚化,从而抑制ASK1和激酶MAPK8[mitogen-activated protein kinase 8,也称为JNK1(c-Jun N-terminal kinase 1)]的信号通路。此外,我们鉴定出源于CFLAR的一个小肽片段(S1)可以有效发挥CFLAR对ASK1的抑制作用。应用CFLAR(S1)治疗可有效改善并逆转小鼠和猴子中的NASH及并发的代谢综合征。综上所述,我们发现,CFLAR是控制NASH疾病进展的关键抑制子。CFLAR(S1)特异性抑制ASK 1激活的作用机制,为开发或筛选NASH的靶向治疗药物提供了可行的新方案。

Nonalcoholic steatohepatitis（NASH）is a progressive disease that is often accompanied by metabolic syndrome and posesa high risk of severe liver damage.However,no effective pharmacological treatment is currently available for NASH.Here we report that CASP8 and FADD（Fas-associating protein with death domain）-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.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.