12-Lipoxygenase as a rate-limiting step to promote brown fat/liver cross talk and suppress hepatosteatosis in high-fat diet fed mice

• Grant number: 21/01311-6
• Support Opportunities: Scholarships in Brazil - Master
• Start date: April 01, 2021
• End date: March 31, 2023
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Luiz Osório Silveira Leiria
• Grantee: Víctor Azevêdo Vieira
• 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

Owing to its capacity of increasing energy expenditure and promoting glucose and triglycerides clearance from circulation, brown adipose tissue (BAT) has become a major therapeutic target to combat diabetes, obesity and related conditions. Besides, BAT also promote beneficial metabolic effects as an endocrine organ, thereby secreting factors that regulate glucose and lipid homeostasis in distal organs. Our previous studies indicate that when stimulated, BAT can secrete a 12-lipoxygenase (12-LOX) product named 12-HEPE, which is able to promote glucose uptake into tissues. Besides, 12-HEPE can also suppress de novo lipogenesis in the liver by suppressing Scd1 activity and expression. Based on such findings we hypothesized that 12-LOX activation in BAT is required for the suppressive effects of cold exposure on hepatic de novo lipogenesis and inflammation. To test this hypothesis, we will test the 12-LOX products' capacity to suppress de novo lipogenesis in vitro, in Hepg2 hepatocytes. We will also test the lipids for their capacity to suppress inflammation in macrophage cell culture, stimulated or not with LPS. The lipid(s) found more capable of suppressing de novo lipogenesis and inflammation in vitro, will be also tested in vivo, by using murine models of obesity and hepatic steatosis induced by high-fat diet. To assess whether 12-LOX activity in BAT is required for the beneficial effects of cold upon the de novo lipogenesis in the liver, we will use a transgenic mice model in which we will delete the 12-LOX enzyme specifically in BAT, and then will induce obesity and hepatic steatosis in those animals with HFD. In this experiment, we expect that 12-LOX knockout mice will be resistant to the beneficial effects of cold exposure in hepatic steatosis. Nevertheless, we expect that this study will allow us to identify new pathways that are modified by 12-LOX products, and that can lead to suppression of de novo lipogenesis and amelioration of hepatic steatosis. (AU)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

VIEIRA, Víctor Azevêdo. Changes in lipid metabolism in the liver during adaptive thermogenesis. 2023. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.