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Therapeutic effects of selective p300 histone acetyl-transferase inhibitor on liver fibrosis
Hyunsik Kim1 (Graduate Student), Soo-Yeon Park1 (Research Assistant Professor), Soo Yeon Lee1 (Research Assistant Professor), Jae-Hwan Kwon1 (Graduate Student), Seunghee Byun1 (Graduate Student), Mi Jeong Kim2 (Research Assistant Professor), Sungryul Yu3 (Associate Professor), Jung-Yoon Yoo 4,# (Associate Professor), Ho-Geun Yoon 1,*,# (Professor)
1Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine,
2Department of Food and Biotechnology, College of Science and Technology Institute of Natural Sciences Korea University,
3Department of Clinical Laboratory Science, Semyung University,
4Department of Biomedical Laboratory Science, Yonsei University MIRAE Campus
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 ther-apeutic avenue for treating liver fibrosis.
Abstract, Accepted Manuscript(in press) [Submitted on November 15, 2022, Accepted on December 27, 2022]
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