Statins, insulin resistance and DM2: interactions between LDL receptor (LDLR) and insulin signaling

• Grant number: 16/04722-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: July 01, 2016
• End date: June 30, 2017
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Mario Jose Abdalla Saad
• Grantee: Felipe Guimarães Pascoal
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Statins are widely used for dyslipidemia treatment. Because these drugs inhibit intracellular cholesterol production, it is believed that they generate, as a secondary effect, an increase in the quantity and activity (up-regulation) of LDL receptors (LDLR) in the cellular surface, as this enhances the absorption of LDL structural cholesterol. Despite their high therapeutic efficacy, statins seem to raise type 2 diabetes mellitus. Although the molecular mechanism for the occurrence of this colateral effect is still unknown, it is supposed that the increase in LDLR expression and activity, due to statin use, may interfere with the insulin signaling cascade. The main goal of this study is to investigate the mechanism through which statins (rosuvastatin) generate insulin resistance, focusing on how insulin signaling is modulated by variations in the LDLR-IR interaction. Materials and Methods: we will study 4 groups of mice: a control group with standard diet and no treatment (PAD-ROS); a group with standard diet and medicated with rosuvastatin (PAD+ROS); a LDLR "knock-out"group with standard diet and no treatment (KO-ROS); and another LDLR "knock-out" group, with standard diet and medicated with rosuvastatin (KO+ROS). Surgical extraction of mice liver will be performed, followed by protein analysis by Immunoblotting and Immunoprecipitation. Additionally, optic microscopical Immunohistochemistry and circulating inflammatory interleukin level analysis will be carried out.