Characterization of the involvement of nutrient sensor mTORC1 in the hepatic steatosis, steatohepatitis, and hepatocarcinoma induced by PTEN deletion into hepatocytes

• Grant number: 17/17582-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: December 01, 2017
• End date: September 30, 2020
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: William Tadeu Lara Festuccia
• Grantee: Mayara Franzoi Moreno
• 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

Abstract

Non-alcoholic fatty liver disease (NAFLD) comprises a group of diseases characterized by exacerbated hepatic liver accumulation progressively varying from a simple steatosis (NAFL) to more serious steatopatite (NASH) and hepatocellular carcinoma (HCC). Several studies have found that the canonical growth factors intracellular PI3K-mTORC2-Akt-mTORC1 signaling pathway actively participates, by mechanisms not yet completely defined, in the development of NAFL-NASH-HCC progression. One of the difficulties, though, in the characterization of mTORC1 specific actions in this progression results from its intense cross-talk with mTORC2. Indeed, mTORC2 is a positive upstream regulator of mTORC1 that, in turn, inhibits mTORC2 activity through a negative feedback on IRS function. To overcome this problem, we propose herein to study the NAFL-NASH-HCC progression in mice with a combined deletion of Raptor (mTORC1 deficiency) and Pten exclusively in hepatocytes. As Pten is positioned downstream to IRS, its deletion promotes the constitutive activation of mTORC2-Akt-mTORC1 pathway without interfering with the negative feedback exerted by mTORC1 on IRS function. For this, mice with deletion of either Pten, or Raptor or both Raptor and Pten exclusively in hepatocytes will be evaluated for glucose (glucose and insulin tolerances) and lipid metabolism (lipogenesis, lipolysis, fatty acid oxidation and TAG secretion), liver and serum lipid profile (lipidomics), mitochondrial and peroxisome contents and function, oxidative stress, resident leukocytes by FACS, intracellular insulin and proinflammatory signaling, gene expression profile, and inflammatory cytokines.

Scientific publications

(5)

(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)

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, NOV 2021. (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)

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, AUG 2021. (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)

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, APR 2019. (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. 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, p. 11-pg., 2021-05-19. (19/17660-0, 16/23169-9, 17/23040-9, 15/22983-1, 17/17403-1, 19/04271-5, 13/07937-8, 17/17582-3, 15/19530-5, 17/12260-8, 18/11156-5, 15/13508-8, 19/01763-4)

PEIXOTO, ALBERT S.; MORENO, MAYARA F.; CASTRO, ERIQUE; PERANDINI, LUIZ A.; BELCHIOR, THIAGO; OLIVEIRA, TIAGO E.; VIEIRA, THAYNA S.; GILIO, GUSTAVO R.; TOMAZELLI, CAROLINE A.; LEONARDI, BIANCA F.; et al. Hepatocellular carcinoma induced by hepatocyte Pten deletion reduces BAT UCP-1 and thermogenic capacity in mice, despite increasing serum FGF-21 and iWAT browning. JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY, v. N/A, p. 13-pg., 2023-07-05. (17/12260-8, 21/14419-0, 19/17660-0, 20/10215-8, 15/19530-5, 20/04159-8, 19/04271-5, 18/03418-0, 22/02123-1, 17/17582-3, 17/23040-9, 19/01763-4, 15/22983-1, 20/09399-7)