Omega-3 lipid metabolites effects on histomorphological parameters of livers from mice with non-alcoholic fatty liver disease

• Grant number: 21/01607-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2021
• End date: March 31, 2022
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Luiz Osório Silveira Leiria
• Grantee: Matheus Henrique Pereira da Silva
• 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

Obesity is related to the onset of several comorbidities, including type-2 diabetes, non-alcoholic fatty liver disease (NAFLD), hypertension, and dyslipidemia. NAFLD is one of the most prevalent complications derived from obesity, and its incidence is growing worldwide.NAFLD is characterized by an elevated accumulation of fat in form of triacylglycerol (TAG) in the liver, while in more severe cases, it also involves inflammation and fibrosis. Previous studies suggest that activation of brown adipose tissue (BAT) either through cold exposure or by genetic/pharmacological interventions is associate with suppression of hepatic de novo lipogenesis, thereby reducing TAG accumulation in liver. The oxylipin 12-HEPE is an omega-3 lipid metabolite resultant from 12-lipoxygenase (12-LOX) oxidative action, which is overproduced in BAT under cold and released into the circulation and sustains thermogenesis by promoting glucose uptake into the tissues. The identification of other BAT-released factors that mimic the beneficial effects of cold exposure is a strategy that can lead to novel therapeutic alternatives for combating metabolic diseases. Our hypothesis is that, in addition to 12-HEPE, other omega-3 12-LOX products such as 14-HDHA and Maresin-2 are able to suppress hepatic lipogenesis. In this study we aim to evaluate the histomorphological changes induced by the 12-LOX products 14-HDHA, 12-HEPE, and Maresin-2 in obese mice fed with high-fat diet and supplemented with fructose. Those mice will be treated for 10 days with the aforementioned lipids, and after that the liver and adipose tissue depots will be collected for histomorphological and molecular studies, while plasma will be collected for measurements of transaminases (ALT and AST) levels, and lipid profile (free fatty acids, TAG, HDL, LDL). Citokynes levels will be also assessed.