HDL-mediated reverse cholesterol transport as a regulator of hepatic lipogenesis

• Grant number: 24/10752-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2024
• End date: September 30, 2027
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Luiz Osório Silveira Leiria
• Grantee: Gabriela Gonzalez Segura
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most prevalent chronic liver disease in the world, and is driven by the increase in obesity and type 2 diabetes mellitus (T2DM). These conditions, exacerbated by a sedentary lifestyle and high-fat diets, lead to the accumulation of free fatty acids in the liver, causing imbalances in lipid metabolism, lipotoxicity, and liver damage. In MAFLD, circulating levels of HDL are reduced. Furthermore, there is a decrease in the levels of docosahexaenoic acid (DHA) in the liver, a highly unsaturated fatty acid, which is produced in adipose tissue through the Fads2 desaturase. Conversely, it is known that in negative energy balance conditions, such as in physical exercise and cold exposure, there is an increase in HDL levels, and furthermore our preliminary data indicates that DHA levels are increased in the livers from cold exposed mice. Our preliminary also suggests that mice treated with a high-fat diet displays lower levels of DHA in the liver and serum HDL. The objective of this work will be to evaluate whether HDL-mediated reverse cholesterol transport (RCT) reduces hepatic lipogenesis and improves hepatic steatosis through the transport of adipose secreted DHA. A clinical study will be carried out parallel to the preclinical one. The clinical study will involve collecting liver and blood samples from patients diagnosed with MAFLD for histological, biochemical, lipidomic, and genetic evaluations. In the preclinical study, mice with deletion of Apoa1, which prevents HDL from carrying out reverse cholesterol transport (RCT), and Fads2 adipo-KO mice, which reduces the production of DHA in adipose tissue, will be used. Biochemical, morphological, and molecular tests will be carried out on these animals, as well as lipidomic analyses to identify the main lipid species transported from adipose tissue to the liver. Furthermore, it will be investigated whether the anti-steatotic effect of physical exercise depends on HDL-mediated RCT. The importance of this study lies in clarifying the molecular mechanisms linking RCT and the regulation of hepatic lipogenesis, potentially providing new therapeutic approaches to treat MAFLD.