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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Therapeutic effects of selective p300 histone acetyl-transferase inhibitor on liver fibrosis

  • Hyunsik Kim (Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine) ;
  • Soo-Yeon Park (Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine) ;
  • Soo Yeon Lee (Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine) ;
  • Jae-Hwan Kwon (Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine) ;
  • Seunghee Byun (Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine) ;
  • Mi Jeong Kim (Department of Food and Biotechnology, College of Science and Technology Institute of Natural Sciences Korea University) ;
  • Sungryul Yu (Department of Clinical Laboratory Science, Semyung University) ;
  • Jung-Yoon Yoo (Department of Biomedical Laboratory Science, Yonsei University MIRAE Campus) ;
  • Ho-Geun Yoon (Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine)
  • Received : 2022.11.15
  • Accepted : 2022.12.27
  • Published : 2023.02.28
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Abstract

Liver fibrosis is caused by chronic liver damage and results in the aberrant accumulation of extracellular matrix during disease progression. Despite the identification of the HAT enzyme p300 as a major factor for liver fibrosis, the development of therapeutic agents targeting the regulation of p300 has not been reported. We validated a novel p300 inhibitor (A6) on the improvement of liver fibrosis using two mouse models, mice on a choline-deficient high-fat diet and thioacetamide-treated mice. We demonstrated that pathological hall-marks of liver fibrosis were significantly diminished by A6 treatment through Masson's trichrome and Sirius red staining on liver tissue and found that A6 treatment reduced the expression of matricellular protein genes. We further showed that A6 treatment improved liver fibrosis by reducing the stability of p300 protein via disruption of p300 binding to AKT. Our findings suggest that targeting p300 through the specific inhibitor A6 has potential as a major therapeutic avenue for treating liver fibrosis.

Keywords

Acknowledgement

We thank Dr. Jae-woo Kim for providing the LX2 cell line. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MIST) (No. 2018R1A5A2025079 and 2020R1A2C3003303 to H.-G.Y.).

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