Involvement of cholesterol synthesis in the progression of Non-Alcoholic Liver Disease

• Grant number: 23/04509-7
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: May 01, 2023
• End date: July 31, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: William Tadeu Lara Festuccia
• Grantee: Natália Monteiro Pessoa
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 20/04159-8 - mTORC2 and mTORC1 biology and involvement in steatosis development and progression to steatohepatitis and hepatocellular carcinoma, AP.TEM

Abstract

NAFLD represents a heterogeneous group of liver diseases that can range from simple steatosis (NAFL, accumulation of lipids exceeding 5 to 10% of liver mass), to more severe conditions such as steatohepatitis (NASH), cirrhosis and cellular hepatocarcinoma (HCC). In a preliminary study we found that the development of NAFL and progression to NASH induced by PTEN deletion in hepatocytes is associated with an increase in the synthesis of fatty acids, cholesterol and ceramides in the liver. These findings motivated us to investigate during my Masters, the impact of the inhibition of cholesterol synthesis with atorvastatin in the development of NAFL and progression to NASH induced by Pten deletion in hepatocytes. So far, our main findings indicate that inhibition of cholesterol synthesis with atorvastatin protects mice from liver steatosis, fibrosis and inflammation found upon the NASH induced by Pten deletion in hepatocytes. Therefore, during my Ph.D., we aim to investigate the molecular mechanisms underlying these protective actions of atorvastatin in the development of NAFL and NASH induced by Pten deletion in hepatocytes. We will also test the effects of HMGCR inhibition with atorvastatin in a different mouse model of NAFL and NASH induced by intake of high sucrose diet associated with treatment with the carcinogen CCL4 and investigate the involment of NLRP3 inflammasome as mediator of cholesterol deleterious actions in the liver. In these protocols, mice will be evaluated for body weight, food intake and energy efficiency, glucose homeostasis (GTT, ITT, PTT), liver mass and histology (H/E), fibrosis (Picrosirius), inflammation (TNF±, IL-1b, IL -6 and IL-10), intracellular insulin signaling (total and phosphorylated Western blot Akt), lipidome (mass spectrometry), gene expression profiling (qPCR), synthesis of fatty acids, cholesterol and glycerol 3-phosphate, and of key enzymes involved in these processes (FAS, ACC, ACLY, PEPCK and GyK, among others). (AU)

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)

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)