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Characterization of mTORC2 role in the hepatic steatosis, steatohepatitis and hepatocellular carcinoma progression induced by PTEN deletion in hepatocytes

Grant number: 17/23040-9
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2018
Effective date (End): November 30, 2021
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal researcher:William Tadeu Lara Festuccia
Grantee:Álbert Souza Peixoto
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:15/19530-5 - Involvement of the nutrient sensor mTOR in the development of obesity associated chronic metabolic diseases, AP.TEM

Abstract

Visceral obesity is associated with the development of several chronic metabolic diseases such as non-alcoholic fatty liver disease (NAFLD), a group of progressive liver complications that comprises steatosis (NAFL), steatohepatitis (NASH), cirrhosis and hepatocarcinoma (HCC). Several studies indicate that lipogenesis, inflammation, oxidative stress and insulin resistance contribute significantly to the development of NAFLD. In the current project, we will investigate the role of mTORC2, an upstream regulator of Akt, in the NAFL-NASH-HCC progression induced by Pten deletion and therefore hyperactivation of the PI3K-Akt-mTORC1 pathway in hepatocytes. In this sense, C57BL6/J mice controls or bearing in hepatocytes genetic deletion of Pten associated or not with the deletion of Rictor, which is essential for mTORC2 activity (Pten/Rictor double flox) (Cre albumin) will be evaluated by body weight, food intake, glucose and insulin tolerance, hepatic mass, lipid (de novo lipogenesis, TAG synthesis and VLDL secretion) and glucose metabolism (gluconeogenesis and glycogen synthesis and degradation), cell proliferation, steatosis, mitochondrial morphology and function, inflammation (leukocyte infiltration, cytokine and lipid mediators content), intracellular insulin and Toll like receptor-NFkB signaling, oxidative stress, phosphoproteome, lipid composition (lipidomics), fibrosis and tumorigenesis.

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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)
ANDRADE, MAYNARA L.; GILIO, GUSTAVO R.; PERANDINI, LUIZ A.; PEIXOTO, ALBERT S.; MORENO, MAYARA F.; CASTRO, ERIQUE; OLIVEIRA, TIAGO E.; VIEIRA, THAYNA S.; ORTIZ-SILVA, MILENE; THOMAZELLI, CAROLINE A.; CHAVES-FILHO, ADRIANO B.; BELCHIOR, THIAGO; CHIMIN, PATRICIA; MAGDALON, JULIANA; IVISON, RACHAEL; PANT, DEEPTI; TSAI, LINUS; YOSHINAGA, MARCOS Y.; MIYAMOTO, SAYURI; FESTUCCIA, WILLIAM T. PPAR gamma-induced upregulation of subcutaneous fat adiponectin secretion, glyceroneogenesis and BCAA oxidation requires mTORC1 activity. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1866, n. 8 AUG 2021. Web of Science Citations: 0.
OLIVEIRA, TIAGO E.; CASTRO, ERIQUE; BELCHIOR, THIAGO; ANDRADE, MAYNARA L.; CHAVES-FILHO, ADRIANO B.; PEIXOTO, ALBERT S.; MORENO, MAYARA F.; ORTIZ-SILVA, MILENE; MOREIRA, RAFAEL J.; INAGUE, ALEX; YOSHINAGA, MARCOS Y.; MIYAMOTO, SAYURI; MOUSTAID-MOUSSA, NAIMA; FESTUCCIA, WILLIAM T. Fish Oil Protects Wild Type and Uncoupling Protein 1-Deficient Mice from Obesity and Glucose Intolerance by Increasing Energy Expenditure. MOLECULAR NUTRITION & FOOD RESEARCH, v. 63, n. 7 APR 2019. Web of Science Citations: 4.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.