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Regulation of the expression of microRNAs by intracellular peptides in the induction of non-alcoholic steatohepatitis in knockout mice for EP24.15

Grant number: 19/15965-8
Support type:Scholarships in Brazil - Master
Effective date (Start): November 01, 2019
Effective date (End): January 31, 2021
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Alice Cristina Rodrigues
Grantee:Bruna de Araújo Cardoso dos Santos
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:16/04000-3 - Pharmacology of oligopeptidases and intracellular peptides, AP.TEM

Abstract

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of diseases ranging from the presence of hepatic steatosis (fat accumulation in the hepatic parenchyma without inflammation) in the absence of excessive alcohol consumption to steatohepatitis, characterized by steatosis along with the balloonization of the hepatocyte and lobular inflammation, and may progress in the long term to fibrosis, cirrhosis and hepatocellular carcinoma. Knockout mice for the enzyme thimet-oligopeptidase (EP24.15 or THOP - / -) are resistant to the induction of obesity and DHGNA by a hyperlipidic diet, in addition to altering the expression of microRNAs previously associated with NAFLD. It has recently been shown that peptides processed by thimet oligopeptidase can prevent the maturation of the microRNAs. However, there are no studies in the literature that associate the interaction between peptides and microRNAs with NAFLD that can clarify by which mechanisms the oligopeptidase protects the animal from hepatic steatosis after challenge with a high-fat diet. To try to understand if the deletion of EP24.15 protects the animal from developing steatohepatitis, we will use an animal model of induction with choline deficient and hyperlipidic diet, which better mimics the evolution of the disease. If the animal with oligopeptidase deficiency does not develop the condition as the wild animal, we will evaluate liver peptidoma, expression of microRNAs and genes involved in the metabolism of fatty acids. Using an in vitro model of steatosis, we will evaluate the possible role of THOP deletion in the regulation of microRNAs. (AU)