Pirfenidone decreases insulin, glucagon, leptin, plasminogen activator inhibitor 1, preventing nonalcoholic steatohepatitis and myocarditis in an obesity moldel

Introduction and Objectives

Obesity is an epidemic in the world, linked with insulin resistance, nonalcoholic steatohepatitis (NASH), and cardiovascular diseases (CVDs), being the latter main cause of global death. NASH progresses with inflammation with or without hepatic fibrosis, including a hormonal dysregulation. Pirfenidone (PFD) have anti-inflammatory and anti-fibrotic effects. However, its effects on hormonal regulation are completely unknown. The aim of this study was to investigate the effects of PFD on hormonal expression levels, related to the lipids and carbohydrates metabolism in high-fat/high-carbohydrate (HFHC)-diet-induced obese male C57BL/6J mice.

Materials and Patients

Twenty-week-old mice were fed with normal diet (ND, 3.1 kcal/g, n=7) and HFHC (65.1 kcal/g, water with 2.31% fructose and 1.89% sucrose, n=14) diet for 16 weeks; at 8 weeks, seven mice with HFHC were administered PFD (300 mg/kg/day) by gavage. ITT, ELISA, dry-chemistry, ELISA, histologies and SPSS were analyzed.

Results

HFHC mice development NASH and myocarditis with fibrosis in both tissues (P≤0.05). HFHC showed elevated resistin and aspartate aminotransferase (P≤0.05). Parameters significantly increased in HFHC (P≤0.05), were ameliorated by PFD, such as weight (body, liver, and heart), tibia length, epididymal fat, hepatic steatosis, hormones (insulin, glucagon, leptin, plasminogen activator inhibitor 1), lipid profile (total cholesterol, triglycerides, LDL, and VLDL), as well as inflammatory foci and fibrosis in hepatic and cardiac tissue (P≤0.05). Moreover, PFD reduced alanine aminotransferase (P≤0.05).

Conclusions

In the current work, we showed that PFD increases hormone expression levels, which are implicated in the lipids and carbohydrates metabolism, and also improves expression levels of lipid profile and lipoproteins related with NASH and CVDs. These findings contribute and support the potential therapeutic of PFD for the prevention of NASH and cardiovascular disease development induced by obesity.

Ethical statement

All experiments in the mice were done and results were reported in accordance with the ARRIVE guidelines. The protocol was approved by the CUCS Research

Committee at the University of Guadalajara (protocol number: CI-01419).

Declaration of interests

None

Funding

This work was supported by Fondo de Desarrollo Científico de Jalisco

(FODECIJAL, project 8149-2019 to JGC), University of Guadalajara (PROSNI to JGC) and by

Programa de Fortalecimiento a Institutos y Laboratorios de la Universidad de Guadalajara.