ROLE OF ANEXIN A1 IN HEPATOCYTE BIOLOGY: STUDY IN EXPERIMENTAL MODELS OF DIABETES IN VIVO AND IN VITRO

Abstract

Type 1 diabetes (T1D) is a global public health problem, which leads to systemic dysregulations that affect multiple tissues, including serious liver complications. Among liver changes, abnormal deposition of lipid droplets, formation of cytoplasmic and/or nuclear vacuoles, mitochondrial damage, increased production of ROS and death by apoptosis stand out. Patients with DM2 have high plasma levels of annexin A1 (AnxA1) and, in an experimental murine model of DM2, the AnxA1 protein plays a fundamental role in attenuating the effects caused by insulin resistance, such as hepatosteatosis. Despite these important findings, its role has been little explored in hepatocytes in DM1. Thus, the role of AnxA1 will be evaluated in hepatocyte biology through experimental models of DM. DM1 will be induced by the drug streptozotocin (STZ) in wild-type animals and knockouts for this protein. In vitro, we will use the hyperglycemia model in human liver cells of the HepG2 lineage, treated with the AnxA1 mimetic peptide (Ac-2-26) with or without the pan-antagonist of formylated peptide receptors (Boc-2). Various techniques will be performed, such as morphological, immunohistochemical, fluorescence, oxidative stress assays, multiplex using magnetic beads, mitochondrial damage, metabolomics, among others. The results obtained in this project will make it possible to expand the understanding of the action of AnxA1, like its mimetic peptide Ac2-26, in the progression of DM, especially in metabolic and functional changes in the liver.