Thesis defense Enora Le Questel

https://umr1087.testksup.univ-nantes.fr/medias/photo/le-questel-enora-10-_1721035020599-jpg
  • Le 15 October 2024
    Amphi A - Bias 2
    false false
  • 14H

Title of the thesis : Role of Acyl-CoA synthetase family member 3 (ACSF3) in daily hepatic metabolism.

Equipe

Team IV - Cardiometabolic diseases

Directeur de thèse

Bertrand Cariou

Encadrant

Daniel Mauvoisin
 

Rapporteurs

Hervé Guillou, PhD, DR1 INRAE, Chef d'équipe TOXALIM Toulouse
Ute Rogner, PhD, DR CNRS, Institut Cochin, Paris

Examinatrices

Marine Adlanmerini, PhD, CRCN, I2CM, Toulouse
Hélène Duez, PhD, DR2 Inserm, Cheffe d'équipe, Institut Pasteur, Lille


Abstract

Modern lifestyle disrupts our biological rhythms, contributing to the emergence of metabolic complications such as obesity, hepatic steatosis, atherosclerosis, and type-2 diabetes. The hepatic circadian clock (CC) and feeding rhythm coordinate daily metabolism, notably via post-translational modifications (PTM) such as lysine malonylation. This PTM consists in the addition of a malonyl group on protein lysine residues. Increased in mice with hepatic steatosis, malonylation is also disrupted in the liver of CCdeficient models. In addition, the inhibition of ACSF3, a.k.a. the mitochondrial malonylation regulator, shortens the CC period in vitro. Thus, the main hypothesis is: Malonylation is a link between the CC and daily hepatic metabolism. Using different diets and/or feeding schedule in mice, we showed that daily malonylation is rhythmic, controlled by feeding behaviour, and disrupted by high-fat diet, concomitantly with ACSF3 levels. We developed a hepatic Acsf3 knock-down mouse model. Metabolic phenotyping combined with a multi-omic approaches, allowed us to determine the impact of ACSF3 knock down in daily hepatic metabolism regulation and, to decipher the associated mechanisms. The use of various CC and its regulators bioluminescent reporters enabled us to study the link between ACSF3 and the CC in vitro. Altogether, this work identifies ACSF3 and diurnal malonylation as a regulatory node between the CC and daily hepatic metabolism.

Mis à jour le 30 September 2024.