期刊
NATURE MEDICINE
卷 23, 期 4, 页码 439-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4290
关键词
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资金
- National Science Fund for Distinguished Young Scholars [81425005]
- National Natural Science Foundation [81330005, 81630011]
- National Science and Technology Support Project [2014BAI02B01, 2015BAI08B01]
- National Key Research and Development Program [2013YQ030923-05, 2016YFF0101504]
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.
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