Identification and characterization of 12-hydroxypentaenoic acid receptor (12-HEPE)

• Grant number: 19/02766-7
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2019
• End date: February 28, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Luiz Osório Silveira Leiria
• Grantee: Tiago Tomazini Gonçalves
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 17/08264-8 - Investigation on the mechanisms underlying brown adipose tissue/liver crosstalk for the regulation of hepatic de novo lipogenesis and glucose production, AP.JP

Abstract

It is known that adipose tissue-secreted lipid metabolites, the so called lipokines, are able to induce beneficial effects on glucose and lipoproteins homeostasis. Invariably, these effects are mediated by the G-Protein Coupled Receptors (GPCR), thus activating signaling cascades in a manner similar to the classic hormones. GPCRs are a large family of receptors with seven transmembrane proteins that regulate important biological processes in various tissues. Furthermore, more than 30% of currently marketed medicines targets GPCRs. In a previous study we identified a cold-induced lipokine called 12-HEPE, a lipid metabolite resultant from the 12-lipoxygenase (12-LOX)-catalyzed oxidation of Eicosapentaenoic Acid (EPA). 12-HEPE is biosynthesized in brown adipose tissue under noradrenergic stimuli and is released into the circulation, where it acts in an endocrine and autocrine manner, promoting the uptake of glucose in the Brown Adipose Tissue (BAT) itself and in the skeletal muscle. Furthermore, chronic treatment with 12-HEPE also yielded a reduction in the liver triglyceride content, along with a suppression of the enzyme Scd-1 mRNA expression, one of the major involved in the hepatic triglyceride synthesis. Given the increasing incidence of metabolic syndrome and the lack of effective treatments that can simultaneously improve hyperglycemia and hepatic steatosis, it would be extremely important to identify and characterize the GPCR(s) that binds to 12-HEPE, since this lipid has the ability to simultaneously improve glucose tolerance and suppress hepatic steatosis. The aim of this study is to identify and characterize the 12-HEPE-binding GPCR that mediates the effects of this lipid in BAT and liver. In order to answer our questions, we designed a comprehensive GPCR screening strategy, followed by a study on the signaling pathway triggered by this GPCR. We also aim to delete this GPCR in cells and in mice in order to evaluate its physiological role in glucose and lipid metabolism. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GUIMARAES, RAPHAEL C.; GONCALVES, TIAGO T.; LEIRIA, LUIZ O.. Exploiting oxidized lipids and the lipid-binding GPCRs against cardiometabolic diseases. British Journal of Pharmacology, v. 178, n. 3, DEC 2020. (19/02766-7, 20/05040-4, 18/25053-3, 17/08264-8)