Ketogenic diet disrupts BDH1-mediated ketone metabolism and causes myocardial dysfunction in mice

Ketogenic diet (KD), recognized for its multiple metabolic benefits, such as enhanced glycemic homeostasis and weight loss, also imposes intricate influences on cardiac substrate utilization. While KD is effective in reducing blood glucose levels and improving insulin sensitivity, its long-term effects on myocardial ketone body (KB) metabolism remain insufficiently investigated, particularly in relation to cardiac remodeling. In the present study, we found that the KD-based nutritional intervention caused considerable cardiac hypertrophy, altered FAs and KBs metabolic pathways and impaired cardiac function, potentially through the repression of BDH1 protein, which is crucial for the utilization of β-hydroxybutyrate (β-OHB). Additionally, mice with cardiac muscle-specific <em>Bdh1</em> manipulation exhibited cardiac dysfunction after fasting, possibly due to histone methylation modifications. We established several diabetic models using streptozotocin (STZ), <em>db/db </em>transgenic mice, and a combination of STZ and a high-fat diet (HFD). We confirmed that these diabetic models exhibited significant alterations in cardiac ketone body metabolism and BDH1 expression. In summary, our study highlights that the downregulation of BDH1 induced by the ketogenic diet is associated with disrupted myocardial ketone utilization and may lead to myocardial structure and function impairment. Furthermore, the loss of BDH1 can also aggravate cardiac dysfunction during fasting by histone modifications.