Influence of APOB variants on binding and uptake by cellular HepG2 receptors

• Grant number: 21/11655-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2021
• End date: October 31, 2022
• Field of knowledge: Health Sciences - Pharmacy - Toxicological Analysis
• Principal Investigator: Mario Hiroyuki Hirata
• Grantee: Isabella Junqueira Costa
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 16/12899-6 - Genomics, epigenomics and pharmacogenomics characterization of familial hypercholesterolemia in the Brazilian population, AP.TEM

Abstract

The molecular bases of monogenic hypercholesterolemia are associated with: 1. reduced activity of the low-density lipoprotein (LDLR) receptor, consequently with low LDL plasma clearance. 2. The conformational alterations of Apolipoprotein B 100 (ApoB-100), the main LDL protein, responsible for binding to the receptor, which alters affinity, which also leads to low plasma removal of LDL (ANDERSEN, L. H. et al, 2016). 3. hyperactivity of the pro-protein convertase subtilisin/kexin 9 (PCSK9), which is responsible for recycling the LDL receptor, its increased action leads to greater degradation of the LDL receptor, preventing reuse, reducing availability, which leads to lower plasma removal of LDL (ABIFADEL et al, 2003), consequently to the increase in circulation, other proteins also collaborate with the disease phenotype, but to a lesser extent (DEFESCHE et al., 2017; FALUTI et al, 2017) . The study of the APOB gene is of relevant importance, considering the role of its products in the control of circulating cholesterol associated with the risk of developing cardiovascular diseases. In the present study we intend to select and evaluate the ApoB variants that lead to conformational alteration of the protein, in silico, (BORGES, JB et al., 2019) and to select 4 main pathogenic variants of ApoB that lead to conformational alteration and evaluate the influence on the physiological process of binding and uptake in HepG2 cell model. (AU)