Diet-Induced Ceramide Remodeling as a Mechanistic Link to Cardiac Metabolic Dysfunction.

Background/Objectives: Dietary patterns characterized by excess saturated fat intake contribute to obesity, type 2 diabetes, and cardiac metabolic dysfunction. Ceramides, bioactive sphingolipids synthesized in response to nutrient overload, have emerged as key molecular mediators linking dietary lipid composition to alterations in cardiac metabolic signaling. This review aims to integrate current evidence on diet-induced ceramide remodeling and its impact on intracellular pathways regulating cardiac metabolism. Methods: We analyzed experimental and clinical studies investigating the effects of high-fat and Western-type diets on myocardial ceramide synthesis, lipidomic remodeling, and downstream signaling pathways. Evidence from animal models, genetic and pharmacological interventions, nutritional studies, and circulating biomarker analyses was examined to delineate mechanistic and translational insights. Results: Saturated fatty acid excess, particularly palmitate, activates the de novo ceramide synthesis pathway in the myocardium, promoting accumulation of specific ceramide species. This remodeling impairs insulin signaling through Akt inhibition, protein phosphatase 2A activation, and PKCζ-dependent mechanisms, contributing to cardiac metabolic inflexibility. Ceramides further disrupt mitochondrial function by altering electron transport chain activity, increasing reactive oxygen species production, and modulating mitophagy and apoptotic signaling. Lipidomic studies highlight species-specific effects, with C16-ceramides frequently associated with adverse metabolic and cardiovascular outcomes, whereas very-long-chain ceramides may exert distinct functional roles. Circulating ceramide profiles have also been linked to diet-associated cardiovascular risk. Conclusions: Diet-induced ceramide remodeling represents a central molecular axis connecting dietary lipid excess to altered cardiac metabolic signaling. Targeting sphingolipid metabolism through nutritional or pharmacological strategies may offer novel opportunities for preventing and managing diet-associated cardiac dysfunction.