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

PX Wang, YX Ji, XJ Zhang, LP Zhao, ZZ Yan… - Nature medicine, 2017 - nature.com
PX Wang, YX Ji, XJ Zhang, LP Zhao, ZZ Yan, P Zhang, LJ Shen, X Yang, J Fang, S Tian…
Nature medicine, 2017nature.com
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 …
Abstract
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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