Evaluation of the development of steatohepatitis induced by a methionine and choline deficient diet in different strains of mice

• Grant number: 23/07267-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2023
• End date: November 30, 2024
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Márcia Regina Nagaoka
• Grantee: Giovana Sambrana Castilho
• Host Institution: Instituto de Saúde e Sociedade (ISS). Universidade Federal de São Paulo (UNIFESP). Campus Baixada Santista. Santos , SP, Brazil

Abstract

Non-alcoholic fatty liver disease (NAFLD) stands as the leading cause of liver disorders worldwide, affecting approximately 25% of the population. It encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), a more severe form. The progression from steatosis to NASH involves lipotoxicity, oxidative stress, and inflammation. Recently, we investigated kinins in oxidative stress in NASH induced by a methionine and choline-deficient (MCD) diet. The main histological features of NASH include steatosis, lobular inflammation, and hepatocyte ballooning. However, the MCD model in Swiss mice exhibited liver lesions and oxidative stress but lacked hepatocyte ballooning. As per the literature, the response to the MCD diet varies among animal strains due to differential susceptibility. We also observed weight loss in MCD-fed animals, despite higher food intake compared to controls fed with AIN-76, suggesting a hypermetabolic state.This project aims to compare susceptibility to NASH in two strains of mice, the inbred (C57BL/6J) and the outbred (Swiss). NASH will be induced by a 4-week MCD diet in both strains, with two control groups fed AIN-76 and another with Purina. We will evaluate metabolic parameters (blood glucose, cholesterol, and triacylglycerols), liver damage markers (alanine and aspartate aminotransferases, ALT and AST), and histological parameters (steatosis, inflammatory infiltrate, and hepatocyte ballooning). Behavioral assessments (neurotoxicity test, open field test, object recognition test, plus maze test) and oxidative stress (catalase, superoxide dismutase, glutathione S-transferase, and malondialdehyde) will also be evaluated.This study is expected to broaden the understanding of variability in NASH susceptibility between mouse strains and identify factors in the pathogenesis of NASH.