Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPK

Hepatology Communications
Ana Sandoval-RodriguezJuan Armendariz-Borunda

Abstract

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 f...Continue Reading

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Citations

Jul 6, 2020·Cardiovascular Drugs and Therapy·Jorge Gutiérrez-CuevasJuan Armendáriz-Borunda
Oct 11, 2020·Cells·Martijn R MolenaarJ Bernd Helms
Oct 18, 2020·Antioxidants·Marina Galicia-MorenoJuan Armendariz-Borunda
Mar 18, 2021·Canadian Journal of Gastroenterology & Hepatology·Marina Galicia-MorenoJuan Armendariz-Borunda
Apr 4, 2021·Cells·Jorge Gutiérrez-CuevasJuan Armendariz-Borunda
Jun 1, 2021·Immunopharmacology and Immunotoxicology·May Ahmed ShawkiRiham S Said
Jun 5, 2021·Scientific Reports·Rebeca Escutia-GutiérrezJuan Armendáriz-Borunda
Aug 8, 2021·International Journal of Molecular Sciences·Hugo Christian Monroy-RamirezJuan Armendariz-Borunda

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Methods Mentioned

BETA
transfections
Assay
electrophoresis
nuclear translocation
transfection

Software Mentioned

CHIMERA
MODEL
SWISS
SwissDock
Image Lab
EADock DSS engine
Image
Graph Prism
ProPlus

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