As sepsis hits 49 million people per year, killing 11 million of them, it is
the most urgent unmet medical condition of today. In the best mouse
model of sepsis, the CLP model, we have found that lethality is linked to
loss of function of the transcription factor PPARa in hepatocytes. PPARa
is the coordinator of fatty acid beta oxidation and ketogenesis, i.e. the
transformation of free fatty acids (FFAs) into acetyl-coA and ketone
bodies (KBs). In sepsis, FFAs are massively released from fat and so they
accumulate in tissues because they are not transformed to KBs. These
latter are essential to prevent coma and heart failure. RNA sequencing
(RNASEQ) of livers from septic mice, revealed that the decline in PPARa
mRNA is strongly predicted to depend on a progressive failure of HNF4a,
a key transcriptional regulator of hepatocyte differentiation. So, in
sepsis, the loss of HNF4a function leads to de-differentiation of
hepatocytes, which is reflected in decreased expression of many other
genes, i.e. cytochrome p450 (Cp450) coding genes. The cause of the
HNF4a failure and de-differentiation of the liver and the role it plays in
the progression of sepsis form the basis of this project.Using mice, we
will investigate the role that HNF4a plays in sepsis and on the
mechanism of the loss of function of HNF4a: we will study basic aspects
of the transcription factor biology of HNF4a during sepsis, and the role
of FFAs in the inhibition of HNF4a by spatial RNASEQ transcriptomics
using normal, mutant and humanized mice. The impact of HNF4a
problems on Cp450 function will be studied as a cause of rise of
endogenous metabolites and their role in sepsis. New HNF4a ligands will
be identified by screening and a new sepsis biomarker defined.
Therapeutic interventions will be explored using PPARa stimuli and KBs,

and validation of our data towards human sepsis will happen via a two-
step strategy involving a pig sepsis model and the collection and study

of human sepsis liver biopsies.