Sex hormone signaling in hepatic metabolic memory

Sex hormones are considered as the main drivers for hepatic sexual dimorphism, with male and female livers displaying important differences in physiological and pathological processes. This is exemplified by the higher prevalence of nonalcoholic steatohepatitis (NASH) in men. While being a core element of disease management, weight loss and the associated benefits on hepatic inflammation and fibrosis are difficult to sustain on the long run, and relapses are common. Preclinical research supports the existence of a hepatic memory: metabolic insults lead to persistent epigenetic changes in the liver. Whether these chromatin modifications are involved in NASH recurrence is however unknown. In addition, their sex-specificity as well as the role of sex hormones in this process remain to be investigated. This project will combine rodent models with genome-wide omics approaches to explore the role of sex hormone signaling in NASH relapses associated with weight regain after weight loss, shedding light on the sex-specific functional consequences, molecular mechanisms and reversibility of hepatic metabolic memory.