N-Lactoyl-phenylalanine Improves Cardiac Function in a Mouse Model of Diabetic Cardiomyopathy by Regulating Lipid Metabolism

Diabetic cardiomyopathy (DCM) is one of the most serious complications of diabetes. N-lactoyl-phenylalanine (Lac-Phe), an endogenous metabolite, can promote weight loss and improve glucose homeostasis. This study sought to investigate the therapeutic effect of Lac-Phe on DCM and further explore the underlying mechanism. Type 2 diabetic mice with DCM were treated with Lac-Phe. Lac-Phe enhanced cardiac contractile function, ameliorated pathological remodeling, and reduced lipid accumulation in the heart. In vitro, the effects of Lac-Phe were investigated in H9c2 cells stimulated with high glucose and palmitic acid. Lac-Phe reduced lipid accumulation by decreasing cholesterol synthesis in H9c2 cells. Mechanistically, Lac-Phe promoted the phosphorylation and activation of adenosine monophosphate-activated protein kinase alpha 1 (AMPKα1). Subsequently, activated AMPKα1 phosphorylated and inhibited its downstream target, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), leading to reduced cholesterol synthesis and ultimately ameliorating lipid metabolism imbalance in H9c2 cells. These findings indicate that Lac-Phe improves lipid metabolism in H9c2 cells in DCM through the AMPKα1/HMGCR pathway, thereby enhancing cardiac contractile function and ameliorating pathological remodeling. Lac-Phe may represent a potential therapeutic approach for diabetic cardiomyopathy.