2. Academic Validation
  3. A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques

A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques

  • Sci Transl Med. 2021 Dec 15;13(624):eabg8116. doi: 10.1126/scitranslmed.abg8116.
Xiao-Jing Zhang 1 2 3,  Yan-Xiao Ji 2 3,  Xu Cheng 1 2,  Yanjie Cheng 2 4,  Hailong Yang 1 2,  Junyong Wang 1 2,  Ling-Ping Zhao 2 3,  Yong-Ping Huang 2 5,  Dating Sun 1 2,  Hui Xiang 1 2,  Li-Jun Shen 1 2,  Peng-Long Li 2 3,  Jun-Peng Ma 2 3,  Rui-Feng Tian 1 2,  Juan Yang 1 2,  Xinxin Yao 2 3,  Haibo Xu 6,  Rufang Liao 6,  Li Xiao 7,  Peng Zhang 2 3,  Xin Zhang 2,  Guang-Nian Zhao 2 4,  Xi Wang 1 2,  Man-Li Hu 2 4,  Song Tian 1 2,  Juan Wan 1 2,  Jingjing Cai 8,  Xinliang Ma 9,  Qingbo Xu 10,  Yibin Wang 11,  Rhian M Touyz 12,  Peter P Liu 13,  Rohit Loomba 14,  Zhi-Gang She 1 2,  Hongliang Li 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • 2 Institute of Model Animal of Wuhan University, Wuhan 430071, China.
  • 3 School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 4 Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
  • 5 College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 6 Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
  • 7 Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 8 Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
  • 9 Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19004, USA.
  • 10 Centre for Clinic Pharmacology, The William Harvey Research Institute, Queen Mary University of London, London SE5 9NU, UK.
  • 11 Department of Anesthesiology, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 12 British Heart Foundation Chair in Cardiovascular Medicine, and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.
  • 13 Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.
  • 14 NAFLD Research Center, Division of Gastroenterology and Epidemiology, University of California, San Diego, San Diego, CA 92093, USA.
PMID: 34910548 DOI: 10.1126/scitranslmed.abg8116
Abstract

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease and has become a leading indication for liver transplantation in the United States. The development of effective therapies for NASH is a major unmet need. Here, we identified a small molecule, IMA-1, that can treat NASH by interrupting the arachidonate 12-lipoxygenase (ALOX12)–acetyl-CoA carboxylase 1 (ACC1) interaction. IMA-1 markedly blocked diet-induced NASH progression in both male mice and Cynomolgus macaque therapeutic models. The anti-NASH efficacy of IMA-1 was comparable to ACC inhibitor in both species. Protein docking simulations and following functional experiments suggested that the anti-NASH effects of IMA-1 were largely dependent on its direct binding to a pocket in ALOX12 proximal to its ACC1-interacting surface instead of inhibiting ALOX12 Lipoxygenase activity. IMA-1 treatment did not elicit hyperlipidemia, a known side effect of direct inhibition of ACC enzymatic activity, in both mice and macaques. These findings provide proof of concept across multiple species for the use of small molecule–based therapies for NASH.

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