Background and aim: Obesity is associated with insulin resistance, nonalcoholic steatohepatitis (NASH) and myocardial fibrosis. Peroxisome proliferator-activated receptors (PPARs) regulate carbohydrate and lipid metabolism; improving insulin sensitivity, triglyceride levels, inflammation and oxidative stress. Pirfenidone has anti-inflammatory, antioxidant and antifibrotic effects. Aim, we investigated the molecular effects of prolonged-release pirfenidone (PR-PFD) in ventricular tissue of male C57BL/6J mice with NASH.
Material and methods: All experiments were performed in compliance with the guidelines of the bioterium-CUCS Research Committee at the University of Guadalajara and National Institutes of Health (NIH). Five-week-old mice were fed with normal diet (ND, 18% kcal from fat, n=5) and high-fat/high-carbohydrate (HFHC, 60% kcal from fat, plus 42g/L: 55% fructose y 45% sucrose in water, n=10) diet for 16 weeks of feeding. At 8 week, five mice with HFHC diet were administered PR-PFD (350mg/kg/day). We assessed insulin resistance, oil red o, hematoxylin-eosin, Masson's trichrome and picrosirius staining, western blot, immunohistochemistry, RT-qPCR and data by SPSS.
Results: Mice showed NASH with insulin resistance, myocardial steatosis and fibrosis, which were prevented by PR-PFD. Ventricular tissue of HFHC mice showed increased TNF-α, Nrf2, Desmin, Tgfβ1, Timp1, Collagen-I, Collagen-III, mRNA levels, including NF-kB, Nrf2, α-SMA, Troponin-I, Acox1, Cpt1A and Lxrα protein levels compared to the ND ventricular tissues (P≤0.05). PR-PFD treatment decreased these genes overexpressed by HFHC diet (P≤0.05). PR-PFD overexpressed the Pgc1a mRNA levels and Pparα, Pparγ, Acox1 and Cpt1A protein levels (P≤0.05).
Conclusions: PR-PFD prevents the cardiac steatosis and fibrosis by sobreexpressing Pparα, Pparγ, Acox1 y Cpt1A proteins. PR-PFD is a promising drug for the treatment of cardiac fibrosis induced by NASH.
This work was supported by “Fondo de Desarrollo Científico de Jalisco (FODECIJAL, 8149-2019 and 7941-2019)” and by “Consejo Nacional de Ciencia y Tecnología (CONACYT, 259096)”.
Conflicts of interest: The authors have no conflicts of interest to declare.
