title: Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates.
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.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Pi-Xiao
authors.initials: PX
authors.lastname: Wang
authors.affiliation: Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Yan-Xiao
authors.initials: YX
authors.lastname: Ji
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Ling-Ping
authors.initials: LP
authors.lastname: Zhao
authors.affiliation: Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.|College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Yan
authors.affiliation: Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Shen
authors.affiliation: Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Division of Cardiothoracic and Vascular Surgery, Heart-Lung Transplantation Center, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Song
authors.initials: S
authors.lastname: Tian
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Xue-Yong
authors.initials: XY
authors.lastname: Zhu
authors.affiliation: Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.|College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gong
authors.affiliation: Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Qiao-Fang
authors.initials: QF
authors.lastname: Wei
authors.affiliation: Basic Medical School, Wuhan University, Wuhan, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Biomedical Engineering Department, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Biomedical Engineering Department, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wan
authors.affiliation: Biomedical Engineering Department, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: She
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.|College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Zan
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Basic Medical School, Wuhan University, Wuhan, China.|Institute of Model Animal of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001706:Biopsy; D001786:Blood Glucose / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics*; D000229:Dependovirus; D019281:Dimerization; D005260:Female; D055879:Gene Knock-In Techniques; D005822:Genetic Vectors; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007333:Insulin Resistance / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008875:Middle Aged; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014463:Ultrasonography; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D048055:Mitogen-Activated Protein Kinase 8; D048848:MAP Kinase Kinase Kinase 5