Attenuation of Palmitic Acid–Induced Lipotoxicity by Chlorogenic Acid through Activation of SIRT1 in Hepatocytes

Scope Saturated free fatty acids (FFAs) induce hepatocyte lipotoxicity, wherein oxidative stress–associated mitochondrial dysfunction is mechanistically involved. Chlorogenic acid (CGA), a potent antioxidant and anti‐inflammatory compound, protects against high‐fat‐diet‐induced oxidative stress and mitochondrial dysfunction in liver. This study investigates whether CGA protects against FFA‐induced hepatocyte lipotoxicity via the regulation of mitochondrial fission/fusion and elucidates its underlying mechanisms. Methods and results AML12 cell, a non‐transformed hepatocyte cell line, is treated with palmitate. Here, it is shown that CGA prevents palmitate‐induced lipotoxicity by activation of SIRT1 regulated mitochondrial morphology. CGA treatment mitigates oxidative stress and mitochondrial dysfunction, as evidenced by a decrease in reactive oxygen species (ROS) production, and an increase in mitochondrial mass and mitochondrial membrane potential. CGA also significantly decreases Bax expression and thereby reduces mitochondria‐mediated caspase‐dependent apoptosis. Mechanistically, CGA attenuates ROS‐induced mitochondrial fragmentation by inhibiting dynamin‐related protein 1 (Drp1) and enhancing Mfn2 expression. In contrast, the inhibitory effects of CGA on the generation of mitochondrial ROS and Drp1 are blocked by siRNA knockdown of SIRT1. Conclusion Collectively, these findings show that supplementation with CGA protects hepatocytes from FFA‐induced lipotoxicity through activation of SIRT1, which reverses the oxidative stress and dysfunction of mitochondrial biogenesis directly. In the present study, a mechanistic model is proposed in which chlorogenic acid (CGA) suppresses palmitate‐induced lipotoxicity in AML12 hepatocytes. CGA improves palmitate‐induced oxidative stress via activation of SIRT1, and suppresses subsequent mitochondrial dysfunction, therefore attenuating lipotoxicity.