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

Abstract

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.

Melatonin protects mouse testes from palmitic acid‐induced lipotoxicity by attenuating oxidative stress and DNA damage in a SIRT1‐dependent manner

“…Strong evidence indicates that palmitate induces cell apoptosis through the activation of the mitochondria-mediated apoptosis pathway. 54 Consistently, we found that PA activated the mitochondrial apoptosis pathway, including Bcl-2 inhibition and Bax promotion, as well as Caspase3 activation. Furthermore, the beneficial effects of melatonin on mitochondrial function inhibited mitochondrial oxidative apoptosis in the presence of PA.…”

Punicalagin Inhibits Palmitate Acid-induced Lipoapoptosis through Inhibition of ER Stress, and Activation of SIRT1/Autophagy in HepG2 Cells

“…It suggests that Sirtuins regulators have certain potential in preventing diseases related to lipid metabolism. According to the former research, PA induced decreases of SIRT1 [25]. In the present study, our data show that PU protects against cytotoxicity via SIRT1 activation in HepG2 cells (Figure 2A), and silencing SIRT1 significantly increased PA-induced cell death ( Figure 2B), which has not been reported in current studies on liver cells.…”

Breast cancer-associated skeletal muscle mitochondrial dysfunction and lipid accumulation is reversed by PPARG

“…Because lipotoxicity-induced mitochondrial dysfunction has been reported in various clinical contexts (22)(23)(24)(25), and because individuals with cancer have been shown to have increased lipid content in muscle (26,27), we assessed intramyocellular lipid concentration in response to BC-CM using oil red o staining and automated image quantification. Using this methodology, we repeatedly observed a significant increase in intramyocellular lipid staining with EO771-CM, but in no experiment did we observe an increase in response to NF639-CM (Figures 2E -2F).…”