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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 Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2018
Effective date (End): February 28, 2022
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:William Tadeu Lara Festuccia
Grantee:Álbert Souza Peixoto
Host 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


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 (4)
(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)
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; et al. 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, . (15/19530-5, 17/17582-3, 16/07062-0, 17/12260-8, 15/22983-1, 16/23169-9, 15/13508-8, 18/11156-5, 17/23040-9)
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.; et al. PAR gamma-induced upregulation of subcutaneous fat adiponectin secretion, glyceroneogenesis and BCAA oxidation requires mTORC1 activit. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1866, n. 8, . (15/19530-5, 17/17582-3, 13/07937-8, 19/01763-4, 17/12260-8, 15/22983-1, 16/23169-9, 19/04271-5, 15/13508-8, 18/11156-5, 19/17660-0, 17/23040-9, 17/17403-1)
CASTRO, ERIQUE; VIEIRA, THAYNA S.; OLIVEIRA, TIAGO E.; ORTIZ-SILVA, MILENE; ANDRADE, MAYNARA L.; TOMAZELLI, CAROLINE A.; PEIXOTO, ALBERT S.; SOBRINHO, CLEYTON R.; MORENO, MAYARA F.; GILIO, GUSTAVO R.; et al. Adipocyte-specific mTORC2 deficiency impairs BAT and iWAT thermogenic capacity without affecting glucose uptake and energy expenditure in cold-acclimated mice. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, v. 321, n. 5, p. E592-E605, . (16/23169-9, 19/25943-1, 17/23040-9, 15/13508-8, 17/17582-3, 18/03418-0, 17/17403-1, 17/12260-8, 19/01763-4, 19/17660-0, 15/19530-5, 20/09399-7, 19/04271-5, 12/25317-4)
CHAVES-FILHO, ADRIANO B.; PEIXOTO, ALBERT S.; CASTRO, ERIQUE; OLIVEIRA, TIAGO E.; PERANDINI, LUIZ A.; MOREIRA, RAFAEL J.; DA SILVA, RAILMARA P.; DA SILVA, BEATRIZ P.; MORETTI, EDUARDO H.; STEINER, ALEXANDRE A.; et al. Futile cycle of beta-oxidation and de novo lipogenesis are associated with essential fatty acids depletion in lipoatrophy. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1868, n. 3, p. 14-pg., . (16/23169-9, 17/23040-9, 20/04159-8, 18/03418-0, 20/09399-7, 20/12969-0, 19/26473-9, 13/07937-8, 15/19530-5, 18/11156-5, 19/17660-0)

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