PR003051 (Project)

Description:Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state, and cellular dynamics. In the gastrointestinal tract, obesogenic high-fat diets enhance small intestinal stem cell activity and tumorigenesis. However, the impact of ketogenic diets (KD), which contain even higher lipid content but reduce circulating insulin and induce ketogenesis, remains poorly understood. This is particularly relevant for patients with familial adenomatous polyposis (FAP), who face a high risk of small intestinal tumors. Here, we combine dietary, genetic, and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumor burden and shortens survival, independent of ketone metabolites. Through genetic manipulation of the ketogenic pathway, we modulate local and systemic ketone metabolite production; however, neither inhibition nor augmentation of the ketogenic enzyme HMGCS2 nor disruption of ketolysis altered tumorigenesis. Combined intestinal deletion of PPARα/δ/γ attenuates KD-driven ISC expansion, proliferation, and clonogenicity, while inhibition of downstream fatty acid oxidation via CPT1A (Carnitine Palmitoyltransferase 1A) deletion limits adenoma formation specifically under KD, linking tumor initiation to FAO of dietary lipids rather than lipid accumulation. These findings reveal that dietary lipid content, through FAO rather than ketone metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.