Therapeutic potential of targeting ceramide for early cardiometabolic lipotoxicity in vivo study

Ceramides (Cer) drive cardiometabolic disease (CMD) by promoting lipotoxicity and oxidative stress, yet their therapeutic potential remains underexplored. We investigated Cer dysregulation in high-fat diet (HFD) fed rats and evaluated three antidiabetic drugs (Sitagliptin, Liraglutide, Saxagliptin) for Cer-modulating effects. HFD elevated CerC16:0 and CerC18:0 across different tissues (serum, heart and liver), with pronounced cardiac CerC18:0 accumulation (1.37 ± 0.103 nmol/g, p < 0.001). Cer changes preceded alterations in traditional metabolic markers (glucose, cholesterol and triglycerides), suggesting early biomarker potential. In a five weeks pilot study (n = 24), Sitagliptin (Sita) outperformed Liraglutide and Saxagliptin in reducing Cer levels. Extended experiments (n = 48) showed Sita significantly decreased harmful Cer ratios (CerC16:0/24:0, CerC18:0/24:0), reduced oxidative stress and tissue lipid accumulation, while enhancing urinary CerC16:0 excretion index (p < 0.01). Sita restored cardioprotective signaling (eNOS, pAKT, cTnT) and mitigated apoptosis and steatosis. These findings highlight Cer as early indicators of lipotoxic injury and support Sita's potential for CMD therapy through modulation of Cer metabolism, warranting further clinical exploration.