Obiettivo
The metabolic syndrome and its several manifestations have currently taken a tremendous toll on many aspects of society. Nonalcoholic fatty liver disease (NAFLD) is considered the liver component of the metabolic syndrome while atherogenic dyslipidaemia, and especially apolipoprotein B (ApoB)-containing lipoproteins, is considered the major causal mechanism in atherosclerosis initiation and progression. By employing novel humanized mouse models that can be rendered acutely dyslipidemic, we have already demonstrated that,
at the very onset of dyslipidemia, ApoB-containing lipoproteins interact with immune cells in the liver causing immune and metabolic changes, including ectopic lipid deposition. This opened to the idea that the inflammatory response evoked by acute dyslipidemia plays a pivotal role in the initiation of other important lipid-driven diseases such as NAFLD.
Hereafter, we present experiments to elucidate novel mechanisms central to the pathogenesis of NAFLD. We will better define the nature of the innate immune cells that firstly react to a dyslipidemic insult. This will be accomplished by imaging the different hepatic macrophage subsets after transition to dyslipidemia and by examining the physiological changes caused by liver Kupffer cells depletion. Secondly, we will investigate how this initial hepatic response will in turn affect atherosclerosis initiation and progression. We will target atherogenic factors secreted by liver immune cells upon ApoB uptake and inhibit several of them in vivo using neutralizing antibodies. Finally, by employing 2H2O to trace lipids' synthetic rates, we will clarify whether the hepatic lipid accumulation observed in our mice is of endogenous or exogenous sources. This project will yield powerful insights on targetable mechanisms concerning the initiation rather than the end-state of metabolic diseases that are currently endemic to the global population, opening to earlier detection and intervention.
Campo scientifico
Parole chiave
Programma(i)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Meccanismo di finanziamento
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinatore
17177 Stockholm
Svezia