Ferulic acid targets ACSL1 to ameliorate lipid metabolic disorders in db/db mice

Lipid metabolic disorders impair quality of life in humans. Ferulic acid (FA), a ubiquitous phenolic nutrient existing in daily human food, exerts beneficial effects in improving glucose and lipid metabolisms. However, the underlying mechanisms are still unclear. In this study, FA treatment significantly attenuated metabolic disorders in db/db mice. Nontargeted metabolomics results suggested the participation of lipid metabolism regulation. Target fishing identified long-chain acyl-CoA synthase 1 (ACSL1) as the target of FA. FA provided a free fatty acid residue as the substrate of ACSL1 and triggered the mitochondrial membrane distribution of ACSL1. This distribution led to the upregulation of adenosine monophosphate (AMP)/adenosine triphosphate (ATP), which was sensed by AMP-activated protein kinase (AMPK) and in turn caused AMPK phosphorylation, further inhibiting the synthesis of triglyceride and cholesterol. In conclusion, FA might be explored as a potential complementary and alternative nutrient agent targeting ACSL1 to ameliorate lipid metabolism in diabetes.