Docosahexaenoic acid administration improves diabetes-induced cardiac fibrosis through enhancing fatty acid oxidation in cardiac fibroblast

Diabetes mellitus can lead to various complications, including organ fibrosis. Metabolic remodeling often occurs during the development of organ fibrosis. Docosahexaenoic acid (DHA), an essential ω-3 polyunsaturated fatty acid, shows great benefits in improving cardiovascular disease and organ fibrosis, including regulating cellular metabolism. In this study, we investigated whether DHA can inhibit diabetes-induced cardiac fibrosis by regulating the metabolism of cardiac fibroblasts. Type I diabetic mice were induced by streptozotocin and after supplementation with DHA for 16 weeks, clinical indicators of serum and heart were evaluated. DHA administration significantly improved serum lipid levels, cardiac function and cardiac interstitial fibrosis, but not blood glucose levels. Subsequently, immunofluorescences, western blot and label-free quantitative proteomics methods were used to study the mechanism. The results showed that the anti-fibrotic function of DHA was achieved through regulating extracellular matrix homeostasis including ECM synthesis and degradation. Our research demonstrated DHA regulated the energy metabolism of cardiac fibroblasts, especially fatty acid oxidation, and then affected the balance of ECM synthesis and degradation. It suggested that DHA supplementation could be considered an effective adjuvant therapy for cardiac fibrosis caused by hyperglycemia.