Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPK
Nonalcoholic steatohepatitis (NASH) is recognized by hepatic lipid accumulation, inflammation, and fibrosis. No studies have evaluated the prolonged‐release pirfenidone (PR‐PFD) properties on NASH features. The aim of this study is to evaluate how PR‐PFD performs on metabolic functions, and provide...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer Health/LWW
2020-03-01
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| Series: | Hepatology Communications |
| Online Access: | https://doi.org/10.1002/hep4.1474 |
| _version_ | 1797720549578768384 |
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| author | Ana Sandoval‐Rodriguez Hugo Christian Monroy‐Ramirez Alejandra Meza‐Rios Jesus Garcia‐Bañuelos Jose Vera‐Cruz Jorge Gutiérrez‐Cuevas Jorge Silva‐Gomez Bart Staels Jose Dominguez‐Rosales Marina Galicia‐Moreno Monica Vazquez‐Del Mercado Jose Navarro‐Partida Arturo Santos‐Garcia Juan Armendariz‐Borunda |
| author_facet | Ana Sandoval‐Rodriguez Hugo Christian Monroy‐Ramirez Alejandra Meza‐Rios Jesus Garcia‐Bañuelos Jose Vera‐Cruz Jorge Gutiérrez‐Cuevas Jorge Silva‐Gomez Bart Staels Jose Dominguez‐Rosales Marina Galicia‐Moreno Monica Vazquez‐Del Mercado Jose Navarro‐Partida Arturo Santos‐Garcia Juan Armendariz‐Borunda |
| author_sort | Ana Sandoval‐Rodriguez |
| collection | DOAJ |
| description | Nonalcoholic steatohepatitis (NASH) is recognized by hepatic lipid accumulation, inflammation, and fibrosis. No studies have evaluated the prolonged‐release pirfenidone (PR‐PFD) properties on NASH features. The aim of this study is to evaluate how PR‐PFD performs on metabolic functions, and provide insight on a mouse model of human NASH. Male C57BL/6J mice were fed with either normo diet or high‐fat/carbohydrate diet for 16 weeks and a subgroup also fed with PR‐PFD (300 mg/kg/day). An insulin tolerance test was performed at the end of treatment. Histological analysis, determination of serum hormones, adipocytokines measurement, and evaluation of proteins by western blot was performed. Molecular docking, in silico site‐directed mutagenesis, and in vitro experiments using HepG2 cultured cells were performed to validate PR‐PFD binding to peroxisome proliferator–activated receptor alpha (PPAR‐α), activation of PPAR‐α promoter, and sirtuin 1 (SIRT1) protein expression. Compared with the high‐fat group, the PR‐PFD‐treated mice displayed less weight gain, cholesterol, very low density lipoprotein and triglycerides, and showed a significant reduction of hepatic macrosteatosis, inflammation, hepatocyte ballooning, fibrosis, epididymal fat, and total adiposity. PR‐PFD restored levels of insulin, glucagon, adiponectin, and resistin along with improved insulin resistance. Noteworthy, SIRT1–liver kinase B1–phospho‐5′ adenosine monophosphate–activated protein kinase signaling and the PPAR‐α/carnitine O‐palmitoyltransferase 1/acyl‐CoA oxidase 1 pathway were clearly induced in high fat + PR‐PFD mice. In HepG2 cells incubated with palmitate, PR‐PFD induced activation and nuclear translocation of both PPARα and SIRT1, which correlated with increased SIRT1 phosphorylated in serine 47, suggesting a positive feedback loop between the two proteins. These results were confirmed with both synthetic PPAR‐α and SIRT1 activators and inhibitors. Finally, we found that PR‐PFD is a true agonist/ligand for PPAR‐α. Conclusions: PR‐PFD provided an anti‐steatogenic effect and protection for inflammation and fibrosis. |
| first_indexed | 2024-03-12T09:21:08Z |
| format | Article |
| id | doaj.art-4d14eaa986de4f12ad1273fbf1608c98 |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-03-12T09:21:08Z |
| publishDate | 2020-03-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-4d14eaa986de4f12ad1273fbf1608c982023-09-02T14:28:48ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2020-03-014343444910.1002/hep4.1474Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPKAna Sandoval‐Rodriguez0Hugo Christian Monroy‐Ramirez1Alejandra Meza‐Rios2Jesus Garcia‐Bañuelos3Jose Vera‐Cruz4Jorge Gutiérrez‐Cuevas5Jorge Silva‐Gomez6Bart Staels7Jose Dominguez‐Rosales8Marina Galicia‐Moreno9Monica Vazquez‐Del Mercado10Jose Navarro‐Partida11Arturo Santos‐Garcia12Juan Armendariz‐Borunda13Department of Molecular Biology and Genomics Institute for Molecular Biology in Medicine and Gene Therapy Health Sciences University Center University of Guadalajara Guadalajara MéxicoDepartment of Molecular Biology and Genomics Institute for Molecular Biology in Medicine and Gene Therapy Health Sciences University Center University of Guadalajara Guadalajara MéxicoTecnologico de Monterrey Campus Guadalajara Zapopan MéxicoDepartment of Molecular Biology and Genomics Institute for Molecular Biology in Medicine and Gene Therapy Health Sciences University Center University of Guadalajara Guadalajara MéxicoDepartment of Molecular Biology and Genomics Institute for Molecular Biology in Medicine and Gene Therapy Health Sciences University Center University of Guadalajara Guadalajara MéxicoDepartment of Molecular Biology and Genomics Institute for Molecular Biology in Medicine and Gene Therapy Health Sciences University Center University of Guadalajara Guadalajara MéxicoDepartment of Molecular Biology and Genomics Institute for Molecular Biology in Medicine and Gene Therapy Health Sciences University Center University of Guadalajara Guadalajara MéxicoInstitut Pasteur de Lille Universite Lille Inserm, CHU Lille U1011‐EGID Lille FranceChronic‐Degenerative Diseases Institute Health Sciences University Center University of Guadalajara Guadalajara MéxicoDepartment of Molecular Biology and Genomics Institute for Molecular Biology in Medicine and Gene Therapy Health Sciences University Center University of Guadalajara Guadalajara MéxicoIIRSME CUCS University of Guadalajara Guadalajara MéxicoTecnologico de Monterrey Campus Guadalajara Zapopan MéxicoTecnologico de Monterrey Campus Guadalajara Zapopan MéxicoDepartment of Molecular Biology and Genomics Institute for Molecular Biology in Medicine and Gene Therapy Health Sciences University Center University of Guadalajara Guadalajara MéxicoNonalcoholic steatohepatitis (NASH) is recognized by hepatic lipid accumulation, inflammation, and fibrosis. No studies have evaluated the prolonged‐release pirfenidone (PR‐PFD) properties on NASH features. The aim of this study is to evaluate how PR‐PFD performs on metabolic functions, and provide insight on a mouse model of human NASH. Male C57BL/6J mice were fed with either normo diet or high‐fat/carbohydrate diet for 16 weeks and a subgroup also fed with PR‐PFD (300 mg/kg/day). An insulin tolerance test was performed at the end of treatment. Histological analysis, determination of serum hormones, adipocytokines measurement, and evaluation of proteins by western blot was performed. Molecular docking, in silico site‐directed mutagenesis, and in vitro experiments using HepG2 cultured cells were performed to validate PR‐PFD binding to peroxisome proliferator–activated receptor alpha (PPAR‐α), activation of PPAR‐α promoter, and sirtuin 1 (SIRT1) protein expression. Compared with the high‐fat group, the PR‐PFD‐treated mice displayed less weight gain, cholesterol, very low density lipoprotein and triglycerides, and showed a significant reduction of hepatic macrosteatosis, inflammation, hepatocyte ballooning, fibrosis, epididymal fat, and total adiposity. PR‐PFD restored levels of insulin, glucagon, adiponectin, and resistin along with improved insulin resistance. Noteworthy, SIRT1–liver kinase B1–phospho‐5′ adenosine monophosphate–activated protein kinase signaling and the PPAR‐α/carnitine O‐palmitoyltransferase 1/acyl‐CoA oxidase 1 pathway were clearly induced in high fat + PR‐PFD mice. In HepG2 cells incubated with palmitate, PR‐PFD induced activation and nuclear translocation of both PPARα and SIRT1, which correlated with increased SIRT1 phosphorylated in serine 47, suggesting a positive feedback loop between the two proteins. These results were confirmed with both synthetic PPAR‐α and SIRT1 activators and inhibitors. Finally, we found that PR‐PFD is a true agonist/ligand for PPAR‐α. Conclusions: PR‐PFD provided an anti‐steatogenic effect and protection for inflammation and fibrosis.https://doi.org/10.1002/hep4.1474 |
| spellingShingle | Ana Sandoval‐Rodriguez Hugo Christian Monroy‐Ramirez Alejandra Meza‐Rios Jesus Garcia‐Bañuelos Jose Vera‐Cruz Jorge Gutiérrez‐Cuevas Jorge Silva‐Gomez Bart Staels Jose Dominguez‐Rosales Marina Galicia‐Moreno Monica Vazquez‐Del Mercado Jose Navarro‐Partida Arturo Santos‐Garcia Juan Armendariz‐Borunda Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPK Hepatology Communications |
| title | Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPK |
| title_full | Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPK |
| title_fullStr | Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPK |
| title_full_unstemmed | Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPK |
| title_short | Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPK |
| title_sort | pirfenidone is an agonistic ligand for pparα and improves nash by activation of sirt1 lkb1 pampk |
| url | https://doi.org/10.1002/hep4.1474 |
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