P-3 PIRFENIDONE PREVENTS OBESITY-ASSOCIATED NONALCOHOLIC STEATOHEPATITIS AND CARDIAC FIBROSIS THROUGH HORMONAL REPROGRAMMING

Introduction and Objectives

Obesity is now a worldwide epidemic, associated with insulin resistance, nonalcoholic steatohepatitis (NASH), and cardiovascular diseases (CVDs), being the latter main cause of global death. NASH is common among Hispanics, characterized by fatty infiltration, inflammation, with or without hepatic fibrosis, and shows hormonal dysregulation. Pirfenidone (PFD) is an anti-inflammatory, and anti-fibrotic drug. Previously, we reported that PFD has anti-steatosis effects on hepatic and cardiac tissues in mice with NASH, but its mechanisms involved are not completely known. The aim of this study was to investigate the effects of PFD on hormonal regulation in high-fat/high-carbohydrate (HFHC)- diet-induced obese male C57BL/6J mice.

Materials and Methods

At the age of 19-20 weeks, mice were fed with normal diet (ND, 6.2% lipids, 44.2 carbohydrates, 18.6% proteins, n=7) and normal water. Other mice were fed with HFHC (60.3% lipids, 21.4% carbohydrates, 18.3% proteins, n=14) and water with carbohydrates (2.31% fructose and 1.89% sucrose) diet for 16 weeks; at 8 weeks of feeding, seven mice with HFHC diet were administered PFD (300 mg/kg/day) by gavage. Experiments were performed according to the ARRIVE guidelines. Insulin tolerance test (4 h of fasting), ELISA, Hematoxylin-Eosin and Masson staining, and morphometric analysis were performed. Data analysis were evaluated using one-way ANOVA with Tukey post hoc test.

Results

HFHC mice showed NASH with an increase in resistin and aspartate aminotransferase (P0.05). Parameters significantly elevated in HFHC were prevented by PFD such as weight (body, liver, and heart), tibia length, epididymal fat, hepatic steatosis, insulin resistance, hormones (insulin, glucagon, leptin, plasminogen activator inhibitor 1) (Table), triglycerides, total cholesterol, LDL, and VLDL, including inflammatory foci and fibrosis in hepatic and cardiac tissue (P0.05). PFD decreased alanine aminotransferase (P0.05).

Conclusions

PFD decreases metabolic hormones and could be a promising drug for the prevention of obesity-induced NASH and CVDs.