Chronic diseases such as obesity and diabetes are considered as a social and economic burden. The liver is a central organ affected by these conditions resulting in a high level of fat accumulation, defined as Non-Alcoholic Fatty Liver (NAFL). Alarmingly NAFL progresses pejoratively to Non-Alcoholic Steatohepatitis (NASH). The prevalence of NAFL is currently estimated to range 25% in the general population. Therefore, increasing knowledge on this metabolic disorder is a major public health issue. We recently demonstrated that livers from NASH patients displayed a dramatic enrichment of highly polyploid hepatocytes presenting DNA damage stigmata. Fatty hepatocytes divide by endoreplication due to “DNA Damage Response-DDR” activation, this process being considered as an alternative division program (without mitosis) in a context of genomic stress. Our goal is to determine if DDR and/or Polyploidy act as gatekeepers or drivers of NAFL/NASH progression. We will define: (1) The functional characterization of DNA damage signalling during NAFL/NASH development. (2) Metabolic features of polyploid hepatocytes harboring genomic instability. (3) Delineation of key immune actors coupled to DNA damage/polyploid hepatocytes. (4) Predictive values of DDR markers and ploidy profiles during NAFL/NASH sequence. The originality of our project relies on dedicated mouse models recapitulating human disease, the access to well-annotated collections of human liver samples and high technologies that will be applied.