Therapeutic effects of selective p300 histone acetyl-transferase inhibitor on liver fibrosis
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Liver fibrosis is caused by chronic liver damage and results inthe aberrant accumulation of extracellular matrix during diseaseprogression. Despite the identification of the HAT enzyme p300as a major factor for liver fibrosis, the development of therapeuticagents targeting the regulation of p300 has not beenreported. We validated a novel p300 inhibitor (A6) on theimprovement of liver fibrosis using two mouse models, miceon a choline-deficient high-fat diet and thioacetamide-treatedmice. We demonstrated that pathological hall-marks of liverfibrosis were significantly diminished by A6 treatment throughMasson’s trichrome and Sirius red staining on liver tissue andfound that A6 treatment reduced the expression of matricellularprotein genes. We further showed that A6 treatment improvedliver fibrosis by reducing the stability of p300 proteinvia disruption of p300 binding to AKT. Our findings suggestthat targeting p300 through the specific inhibitor A6 has potentialas a major therapeutic avenue for treating liver fibrosis.
Abstract
Liver fibrosis is caused by chronic liver damage and results inthe aberrant accumulation of extracellular matrix during diseaseprogression. Despite the identification of the HAT enzyme p300as a major factor for liver fibrosis, the development of therapeuticagents targeting the regulation of p300 has not beenreported. We validated a novel p300 inhibitor (A6) on theimprovement of liver fibrosis using two mouse models, miceon a choline-deficient high-fat diet and thioacetamide-treatedmice. We demonstrated that pathological hall-marks of liverfibrosis were significantly diminished by A6 treatment throughMasson’s trichrome and Sirius red staining on liver tissue andfound that A6 treatment reduced the expression of matricellularprotein genes. We further showed that A6 treatment improvedliver fibrosis by reducing the stability of p300 proteinvia disruption of p300 binding to AKT. Our findings suggestthat targeting p300 through the specific inhibitor A6 has potentialas a major therapeutic avenue for treating liver fibrosis.
참고문헌 (36)
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