mTORC2 and mTORC1 biology and involvement in steatosis development and progression to steatohepatitis and hepatocellular carcinoma

• Grant number: 20/04159-8
• Support Opportunities: Research Projects - Thematic Grants
• Start date: September 01, 2021
• End date: August 31, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: William Tadeu Lara Festuccia
• Grantee: William Tadeu Lara Festuccia
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Alexandre Alarcon Steiner ; Giuseppe Palmisano ; Isaias Glezer ; Karina Thieme ; Mathieu Laplante ; Naima Moustaid-Moussa ; Sayuri Miyamoto
• Associated research grant(s): 24/19213-9 - Adipocyte Rictor/mTORC2 as mediator of the metabolic effects of the omega 3 polyunsaturated eicosapentanoic acid in obesity and associated metabolic diseases, AP.R SPRINT; 24/01970-8 - Role of macrophages in the determination of liver microenvironment and progression from steatohepatitis (NASH) to hepatocellular carcinoma (HCC), AP.R; 22/00324-0 - Peroxisomes as mediators of the metabolic effects of fish oil in obesity and associated metabolic diseases, AP.R SPRINT; 21/10469-2 - Multi-User equipment approved in grant 20/04159-8: spectrophotometer Synergy, AP.EMU
• Associated scholarship(s): 24/12973-8 - Involvement of adipocyte peroxisomes in the development of obesity and metabolic actions of the PPAR³ agonist pioglitazone in mice, BP.DR; 24/13040-5 - Adrenergic regulation of de novo fatty acids synthesis in brown adipose tissue: role of mTORC2 and 1, BP.DD; 24/09406-4 - Involvement of macrophage mTORC1 and mTORC2 in the development of non-alcoholic fatty liver disease (NAFLD) induced by a diet rich in lipids, sucrose and fructose and carcinogen treatment., BP.DD; + associated scholarships 24/02342-0 - Involvement of nitric oxide and cyclooxygenase-derived metabolites as mediators of fish oil metabolic actions, BP.IC; 23/17140-1 - Effects of constitutive activation of the PI3K-mTORC2-Akt-mTORC1 pathway on the morphology and glucose and lipid metabolism of white and brown adipocytes: studying the individual contributions of mTORC1 and mTORC2., BP.DR; 23/05319-7 - Molecular mechanisms involved in the control of mTORC2 activity by Ric-8B: role of GPCR-G±s-cAMP signalling pathway., BP.DR; 23/04753-5 - Involvement of Branched-Chain Amino Acid (BCAA) metabolism in the development of NAFLD, BP.DR; 23/05190-4 - Charcaterization of the mechanisms underlying the changes in energy balance and metabolism induced by fenofibrate, BP.IC; 23/04509-7 - Involvement of cholesterol synthesis in the progression of Non-Alcoholic Liver Disease, BP.DD; 22/15153-6 - Effects of LPS on mass, morphology and intracellular signaling in white adipose tissue: study of mTORC2 involvement, BP.IC; 22/06279-6 - Effects of leucine supplementation on the development of steatosis and steatohepatitis induced by Pten deletion in hepatocytes, BP.IC; 21/14419-0 - Involvement of hepatocyte and macrophage Rictor/mTORC2 as mediator of LPS metabolic and inflammatory actions in the liver., BP.PD; 22/02123-1 - Involvement of mTORC1 and mTORC2 in the control of the acetylation of proteins related to lipid metabolism in the liver of a model of steatohepatitis., BP.PD; 21/11108-3 - Technical training in crossing and genotyping of genetically modified mice., BP.TT - associated scholarships

Abstract

Evidence gathered in the last decades suggests that lipotoxicity and inflammation, through still not completed defined molecular mechanisms, are the main factors connecting adipose tissue dysfunction to the development nonalcoholic fatty liver disease (NAFLD), a group of liver diseases that comprises from a simple hepatic steatosis (NAFL) to more severe steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). We propose herein to molecularly characterize mTORC1 and mTORC2 biology in hepatocytes and macrophages with a special emphasis in their involvement in the development of NAFL and its progression to NASH and HCC. For this, we will perform hepatocyte and macrophage mTORC1 (Raptor) and mTORC2 (Rictor) gain and loss of function experiments in vitro in primary cells and in vivo in two different mouse models of NAFLD induced either genetically through hepatocyte deletion of PTEN or through the intake of a high-fat, high-cholesterol, high-sucrose, high-fructose diet associated to weekly injections of a carcinogen, denominated altogether as diet-induced NAFLD (DIN). By employing imaging techniques, molecular biology tools and metabolic assays combined with powerful state-of-the-art OMICS (lipidomics, phosphoproteomics, acetylomics and transcriptomics), we will investigate the role of mTORC1 and mTORC2 in the regulation of the following inter-related processes in the NAFL-NASH-HCC progression: lipid metabolism and lipotoxicity; glucose homeostasis and glucotoxicity; endoplasmic reticulum and oxidative stress; inflammation; mitochondrial and peroxisomal oxidative metabolism, reactive oxygen species production and function, autophagy, epigenetics, DNA mutagenesis and repair, and tumorigenesis. (AU)

Scientific publications

(8)

(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)

ORTIZ-SILVA, MILENE; LEONARDI, BIANCA F.; CASTRO, ERIQUE; PEIXOTO, ALBERT S.; GILIO, GUSTAVO R.; OLIVEIRA, TIAGO E.; TOMAZELLI, CAROLINE A.; ANDRADE, MAYNARA L.; MORENO, MAYARA F.; BELCHIOR, THIAGO; et al. Chloroquine attenuates diet-induced obesity and glucose intolerance through a mechanism that might involve FGF-21, but not UCP-1-mediated thermogenesis and inhibition of adipocyte autophagy. Molecular and Cellular Endocrinology, v. 578, p. 11-pg., 2023-09-26. (15/19530-5, 16/05406-3, 16/23169-9, 20/04159-8, 19/01763-4)

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., 2022-12-20. (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)

RODRIGUES, STEPHEN F.; STOKES, KAREN Y.; FESTUCCIA, WILLIAM T.; MARTINS, JOILSON O.. Editorial: Interplay Between Autophagy and Metabolic Syndrome: Causes, Consequences and Therapeutic Challenges. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 9, p. 3-pg., 2021-10-06. (20/07212-7, 19/01763-4, 14/05146-6, 20/03175-0, 20/04159-8, 15/19530-5)

CHAVES-FILHO, ADRIANO B.; DINIZ, LARISSA S.; SANTOS, ROSANGELA S.; LIMA, RODRIGO S.; ORELIANA, HECTOR; PINTO, ISABELLA F. D.; DANTAS, LUCAS S.; INAGUE, ALEX; FARIA, RODRIGO L.; MEDEIROS, MARISA H. G.; et al. Plasma oxylipin profiling by high resolution mass spectrometry reveal signatures of inflammation and hypermetabolism in amyotrophic lateral sclerosis. Free Radical Biology and Medicine, v. 208, p. 14-pg., 2023-08-25. (13/07937-8, 18/18633-3, 19/01763-4, 20/04159-8, 15/19530-5)

CASTRO, ERIQUE; VIEIRA, THAYNA S.; PEIXOTO, ALBERT S.; LEONARDI, BIANCA F.; TOMAZELLI, CAROLINE A.; LINO, CAROLINE A.; OLIVEIRA, TIAGO E.; PESSOA, NATALIA M.; PESSOA, ERIKA V. M.; ABE-HONDA, MARINA A.; et al. Fish Oil and EPA Improve Insulin Sensitivity, in Part Through Adipocyte mTORC2 Activation in Diet-Induced Obese Male Mice. MOLECULAR NUTRITION & FOOD RESEARCH, v. N/A, p. 14-pg., 2025-02-17. (19/00726-8, 24/13040-5, 21/14419-0, 19/01763-4, 22/11234-1, 23/04509-7, 22/02123-1, 23/04753-5, 18/11156-5, 20/04159-8, 19/04271-5, 15/19530-5, 16/23169-9, 20/16656-6, 22/00324-0)

FESTUCCIA, WILLIAM T.. mTORC1 and 2 Adrenergic Regulation and Function in Brown Adipose Tissue. PHYSIOLOGY, v. 40, n. 2, p. 11-pg., 2025-03-29. (19/01763-4, 20/04159-8, 15/19530-5)

GALVAO VALDIVIA, LUIS FELIPE; CASTRO, ERIQUE; DOS SANTOS EICHLER, ROSANGELA APARECIDA; MORENO, MAYARA FRANZOI; DE SOUSA, ERICA; RODRIGUES JARDIM, GIOVANNA FREITAS; PEIXOTO, ALBERT SOUZA; MORAES, MARIA NATHALIA; DE LAURO CASTRUCCI, ANA MARIA; NEDERGAARD, JAN; et al. Cold acclimation and pioglitazone combined increase thermogenic capacity of brown and white adipose tissues but this does not translate into higher energy expenditure in mice. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, v. 324, n. 4, p. 16-pg., 2023-04-01. (17/26651-9, 21/02953-1, 19/01763-4, 20/04159-8, 18/14728-0, 21/03717-0, 17/24615-5, 19/25943-1)

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)