Understanding the role of nuclear receptor HNF4a in sepsis and unravel the mechanisms of its loss-of-function in relation to PPARa failure.

The group of Prof. Libert is trying to understand the molecular mechanisms that are involved in sepsis, with a strong focus on metabolic reprogramming of the liver. We believe that, in sepsis, a starvation response is induced to compensate for the supra-physiological energy need of the immune system and the lack of food intake, but which fails due to a loss-of-function (LOF) of key liver metabolic TFs, such as the GR and PPARα. Because of this failure, elevated lactate and FFAs are no longer converted to glucose and ketone bodies and severe organ damage may occur due to their toxicity. Lise Wyngene found decreasing PPARα levels already starting 6h after sepsis onset. In my project, I am interested in finding the upstream mechanism responsible for this downregulation, with a strong focus on HNF4α: based on bioinformatics tools, we hypothesize that HNF4α (a major driver of PPARα transcription) declines in activity in sepsis. To have more proof of the functional role of HNF4α in sepsis, I will study HNF4aAlbcreERT2Tg/+ and HNF4α-overexpressing mice in the context of survival and use HNF4α agonists and antagonists. I will also study the mechanism(s) of HNF4α LOF in more detail, with a strong focus on protein degradation, alternative splicing and FFA-mediated inhibition. Several tools will be used: FACS, humanized mice, RNA-seq, ELISA, Western analysis.