Molecular determinants of hepatic nutrient homeostasis – NUTRISENSPIK

Coordination of nutrient sensing and signal transduction is essential for achieving metabolic homeostasis. Misalignments of metabolism and signalling underline pathologies including metabolic syndrome and diabetes, having major socio-economic impact. It is important to understand molecular mechanisms implicated to propose novel treatment strategies.
Class III phosphoinositide 3-kinase (PI3K-III) functions in all eukaryotes showing remarkable evolutionary conservation. Its activity is critical for nutrient uptake and metabolism through control of endocytic trafficking, autophagy and lysosomal function. In our recent work, we have revealed a novel crosstalk between PI3K-III and a key nutrient sensing component - insulin signalling. We discovered a novel retro-control loop in which insulin activates PI3K-III activity selective for the endocytosis, having major effect on insulin receptor trafficking and signal transduction. Functionally, it is reflected in striking phenotype of hepatic PI3K-III mutants which are presented with defective glucose metabolism. Importantly, we have discovered that acute hepatic downregulation of PI3K-III alleviates metabolic syndrome in models of insulin resistance and diabetes suggesting that PI3K-III might be a therapeutic target in metabolic conditions. Despite recent progress, our understanding of the PI3K-III regulation in vivo and its implication in human pathology are sketchy.
The overreaching aim of this research proposal is to reveal the molecular mechanisms of NUTRIent SENSing and metabolism as a function of PI3K-III (NUTRISENSPIK). In this program, we will develop and apply approaches to discover novel molecular mechanisms of hepatic PI3K-III regulation at different levels and will elucidate the metabolic activities downstream of PI3K-III. Importantly, we will also characterise the status of hepatic PI3K-III signalling in liver disease both in animal models and in human patient samples. The later will include the conditions of metabolic stress associated with nutritional challenge. Those analyses will provide a crucial information on PI3K-III signalling in common liver pathologies. In the translational perspective, this work might validate the PI3K-III signalling and its novel targets as diagnostic or prognostic markers and will rationalise testing of PI3K-III modulators in the conditions of metabolic disalignment.
When completed, NUTRISENSPIK research program will fill the gap in the knowledge on the role of PI3K-III signalling in metabolic homeostasis, will offer the tools to evaluate the activity of PI3K-III and will provide the evidence on the implication of PI3K-III signalling in human liver pathophysiology. Altogether, those will advance our fundamental understanding of the mechanisms of nutrient sensing in physiology and pathology.