Hepatic Lipid Alterations Mediated by MMP-12 Activity: Implications in Sexual Dimorphism of Metabolic Steatohepatitis in High-fat Diet

• Grant number: 25/03148-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2025
• End date: May 31, 2028
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Carlos Arterio Sorgi
• Grantee: Pedro Nobre Azevedo
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 24/03414-5 - Integrated Analysis of Sphingolipid Metabolism and Extracellular Particle Composition in the Context of a Hight-Fat-Diet: Implications for Lipoproteins, Vesicle Biogenesis, and the Role in Macrophage Response to COVID-19, AP.R

Abstract

Metabolic Dysfunction-Associated Steatohepatitis (MASH) represents a growing public health challenge, with an alarming global prevalence and progression to severe stages such as cirrhosis and hepatocellular carcinoma. Sexual dimorphism in MASH influences susceptibility, progression, and treatment response, requiring in-depth investigation. Recent evidence from our research group indicates the involvement of matrix metalloproteinases (MMPs), particularly MMP-12, in the immunometabolic dysregulation of MASH. MMPs are endopeptidases that, beyond their classical role in extracellular matrix remodeling, play key roles in immune response regulation and inflammation, which are critical processes in MASH pathogenesis. This project aims to investigate the role of MMP-12 in modulating lipid metabolism and its influence on sexual dimorphism in experimental MASH. Using a high-fat diet (HFD)-induced MASH model in C57Bl/6 mice, we will combine bioanalytical lipidomics and proteomics analyses with bioinformatics tools to elucidate the molecular interactions and metabolic pathways affected by MMP-12 activity. Additionally, we will assess the impact of pharmacological inhibition of MMP-12 on MASH progression and hepatic and circulating lipid profiles. We expect to identify potential biomarkers and therapeutic targets, as well as elucidate the molecular mechanisms underlying sexual dimorphism in MASH. The results will contribute to the development of prevention strategies and personalized treatments, with a significant impact on the fields of hepatology and metabolism. (AU)