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The role of liver autophagy in gluconeogenesis and ketogenesis during acute cold stress

Grant number: 24/03229-3
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): October 01, 2024
Effective date (End): September 30, 2025
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:Luiz Carlos Carvalho Navegantes
Grantee:Henrique Jorge Novaes Morgan
Supervisor: Gerald Shulman
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: Yale School of Medicine (YSM), United States  
Associated to the scholarship:21/05848-4 - Sympathetic regulation of hepatic autophagy by CREB/CRTC-2, BP.DR

Abstract

Autophagy is one of the main degradation processes of intracellular components, such as lipids (lipophagy), and it is essential for the maintenance of cellular homeostasis. In the liver, dysregulation of the autophagic process leads to the accumulation of triglycerides and the development of steatosis. Despite its importance, the role of autophagy in hepatic metabolism is still poorly understood. Acute cold stress is a physiological model of autophagy activation where we also find high gluconeogenesis and ketogenesis flux. Using cold stress and autophagy-deficient liver mice as a model, we aimed to investigate the role of autophagy in the control of gluconeogenesis and ketogenesis. In our hypothesis, the absence of autophagy in the liver, during cold stress, leads to a reduction of gluconeogenesis and ketogenesis flux, as well as a greater accumulation of fat in the liver through lipophagy reduction. For this, first we will generate the autophagy-deficient liver mice by crossing Albumin-CRE and Atg7 flox/flox mice generating hepatocyte-specific Atg7 knockout (Alb-Atg7-/-), in the C57Bl/6J background. After, we will analyze the glucose and ketone body metabolism in wild type and Alb-Atg7-/- liver during 6 hours of exposure to cold (4ºC), as well as we will evaluate the flux in vivo of pyruvate carboxylase and citrate synthase using PINTA method - not performed by any Brazilian group. After this time, mice will be euthanized and liver harvested to investigate the gene expressions and proteins involved in gluconeogenesis and ketogenesis using RT-pPCR and western blot. In addition, hepatic lipid content as well as gene expression and proteins involved in the synthesis and degradation of lipids will be assessed.

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