H3K9me3 demethylation by JMJD2B is regulated by pirfenidone resulting in improved NASH
Por:
Rodriguez-Sanabria JS, Rosas-Campos R, Vázquez-Esqueda Á, Palacios-Marin I, Jiménez-Chillaron J, Escutia-Gutiérrez R, Jave-Suarez LF, Galicia-Moreno M, Monroy-Ramirez HC, Cerda-Reyes E, Almeida-López M, Martinez-Lopez E, Herrera LA, Armendáriz-Borunda J and Sandoval-Rodriguez A
Publicada:
21 oct 2024
Ahead of Print:
21 oct 2024
Resumen:
NASH is characterized by hepatic lipid accumulation and inflammation; and JMJD2B-a histone demethylase-upregulation has been linked to its progression. Pirfenidone (PFD) is an antifibrotic agent with anti-inflammatory and antioxidant effects recognized to decrease NASH symptoms. Herein, our aim was to investigate PFD-induced epigenetics mechanisms involving JMJD2B and histone modifications in experimental NASH. Male C57BL/6J mice were fed with normo-diet, or high fat/carbohydrate diet (HF) for 16 weeks. A HF-subgroup was treated with PFD 300 mg/kg/d from week 8th to the end of protocol. Insulin tolerance test and liver and fat histological and biochemical analyses were carried out. Hepatic transcriptome was examined. Liver proteins were studied by western blot (WB) and Chromatin immunoprecipitation. In vitro, lipotoxicity was induced in HepG2 cells and proteins were evaluated using WB. Molecular docking was used to explore binding of PFD to JMJD2B. Mice treated with PFD reduced weight gain, epididymal fat and inflammatory nodules, and steatosis in liver tissue, as well as, improved biochemical test. PFD modified the expression of Jmjd2b, Pparg, Fasn and Srebp1, and restored JMJD2B protein and H3K9me3 repressive mark, both in animal and cell models. PFD increased hepatic enrichment of H3K9me2 and H3K9me3 at the promoter region of Fasn and Srebp1, and Pparg. In HepG2 cells, PFD reduced lipid vacuole accumulation. In silico, PFD interacted with JMJD2B catalytic site. PFD is an epigenetic regulator modifying JMJD2B activity, resulting in reduced NASH traits.
Filiaciones:
:
Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
Departamento Academic Department in Basic Sciences, Universidad Autónoma de Guadalajara, 45129, Zapopan, Mexico
Rosas-Campos R:
Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
Vázquez-Esqueda Á:
Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
Palacios-Marin I:
Institut de Recerca Sant Joan de Déu, Endocrinology, c/ Santa Rosa 39-57, 4ª planta, 08950, Esplugues, Barcelona, Spain
Department of Biochemistry and Physiology, Institut de Biomedicina de la Universitat de Barcelona (IBUB), School of Pharmacy and Food Sciences, Universitat de Barcelona, 08028, Barcelona, Spain
Jiménez-Chillaron J:
Institut de Recerca Sant Joan de Déu, Endocrinology, c/ Santa Rosa 39-57, 4ª planta, 08950, Esplugues, Barcelona, Spain
Department Of Physiological Sciences, School of Medicine, Universitat de Barcelona, 08907, L'Hospitalet-Barcelona, Spain
Escutia-Gutiérrez R:
Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
Jave-Suarez LF:
División de Inmunología, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, 44340, Guadalajara, Mexico
Galicia-Moreno M:
Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
Monroy-Ramirez HC:
Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
Cerda-Reyes E:
Investigation Department, Hospital Central Militar, 11200, Mexico City, Mexico
Almeida-López M:
Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
Martinez-Lopez E:
Department of Molecular Biology and Genomics, Institute of Translational Nutrigenetics and Nutrigenomics, CUCS, University of Guadalajara, 44340, Guadalajara, Mexico
Herrera LA:
Tecnologico de Monterrey, EMCS, 45201, Zapopan, Mexico
Cancer Research Unit, Institute of Biomedical Research, UNAM-National Institute of Cancerology, 04510, Mexico City, Mexico
Armendáriz-Borunda J:
Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
Tecnologico de Monterrey, EMCS, 45201, Zapopan, Mexico
Sandoval-Rodriguez A:
Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, Health Sciences University Center, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico
Green Submitted, gold
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