51. Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates.
- Author
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Wang PX, Ji YX, Zhang XJ, Zhao LP, Yan ZZ, Zhang P, Shen LJ, Yang X, Fang J, Tian S, Zhu XY, Gong J, Zhang X, Wei QF, Wang Y, Li J, Wan L, Xie Q, She ZG, Wang Z, Huang Z, and Li H
- Subjects
- Adolescent, Adult, Animals, Biopsy, Blood Glucose metabolism, Dependovirus, Dimerization, Female, Gene Knock-In Techniques, Genetic Vectors, Hepatocytes metabolism, Humans, Immunohistochemistry, Immunoprecipitation, Insulin Resistance genetics, Interleukin-6 metabolism, Liver diagnostic imaging, Liver pathology, Macaca fascicularis, Male, Mice, Middle Aged, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease pathology, Positron-Emission Tomography, Real-Time Polymerase Chain Reaction, Signal Transduction, Tumor Necrosis Factor-alpha metabolism, Ultrasonography, Young Adult, CASP8 and FADD-Like Apoptosis Regulating Protein genetics, Liver metabolism, MAP Kinase Kinase Kinase 5 metabolism, Mitogen-Activated Protein Kinase 8 metabolism, Non-alcoholic Fatty Liver Disease genetics
- 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.
- Published
- 2017
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