Characterization of the roles for the Hepatocyte Nuclear Factor 4 and lipid metabolism in intestinal inflammation

• Applicant: Dr. Gilles Storelli
• Subject Area: Cell Biology ; Developmental Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 470621046

Inflammatory bowel diseases (IBDs) have a major impact on public health with increasing prevalence worldwide. Although recent studies have linked IBDs with disruptions in lipid homeostasis, the specific pathways remain unclear. We discovered that the loss of a master regulator of lipid metabolism, the Hepatocyte Nuclear Factor 4 (HNF4), recapitulates hallmark features of IBDs in Drosophila, including activated inflammatory signaling and epithelial regeneration. These defects are accompanied by altered expression of genes involved in several pathways of lipid metabolism, suggesting connections between epithelial inflammation and disrupted lipid metabolism. Consistent with this, our preliminary data suggests that HNF4 acts through select pathways of lipid metabolism to suppress intestinal inflammation. I propose an integrative approach that combines Drosophila genetics with transcriptional, metabolic, and physiological studies to dissect the roles for HNF4 and lipid metabolism in suppressing intestinal inflammation. Toward this goal, we will characterize in details the effects of the loss of HNF4 on inflammatory signaling and lipid metabolism in the intestine (Aim 1 and Aim 2). We will then use the power of Drosophila genetics to determine which pathways of lipid metabolism are responsible for activating inflammatory signaling in intestines that lack HNF4 (Aim 3). Finally, we will dissect the molecular mechanisms by which HNF4 and cellular lipid metabolism suppress inflammation (Aim 4). Taken together, the proposed studies could yield important insights into the evolutionarily-conserved mechanisms that regulates cellular lipid metabolism, and into the metabolic origins of IBDs.

• DFG Programme: Research Grants