Ferulic Acid Alleviates Lipotoxicity-induced Hepatocellular Death Through SIRT1 Activating-regulated Autophagy Pathway, and Independently of AMPK and Akt in AML-12 Hepatocytes

Abstract Background: Lipotoxicity-induced cell death plays a detrimental role in the pathogenesis of metabolic diseases. Ferulic acid, widespread in vegetative food, is conferred as a radical scavenger with multiple bioactivities. However, the benefits of Ferulic acid against hepatic lipotoxicity are largely unclear. Here, we investigated the protective role of ferulic acid on palmitate-induced lipotoxicity and clarify its potential mechanisms in AML-12 hepatocytes. Methods: AML-12 mouse hepatocyte was employed and exposed to palmitate to mimic lipotoxicity. Different doses (25, 50, and 100 μM) of ferulic acid were added 2 h before palmitate induction. Cell viability was detected by the measurements of lactate dehydrogenase release, nuclear staining, and the expression of cleaved-caspase3. Intracellular reactive oxygen species and mitochondrial membrane potential were analyzed by fluorescent probe. The potential mechanisms were explored by molecular biological methods, including Western-blot and quantitative real-time PCR, and further verified by siRNA interference. Results: Our data showed that ferulic acid significantly reversed palmitate-induced cell death, rescued mitochondrial membrane potential, reduced reactive oxidative species accumulation, and improved inflammatory factors activation, including IL-6 and IL-1beta. Ferulic acid significantly stimulated autophagy in hepatocytes, while, autophagy suppression blocked ferulic acid-protected lipotoxicity. Ferulic acid-activated autophagy, which was triggered by Sirt1 upregulation, was mechanistically involved in its anti-lipotoxicity benefits. Sirt1 silencing blocked ferulic acid-induced profitable alterations. Conclusions: We demonstrated that ferulic acid was a protective phytochemical against hepatic lipotoxicity in plant-based food, through Sirt1/autophagy pathway. Increasing ferulic acid-enriched food intake is a potential strategy to prevent and/or improve metabolic diseases with lipotoxicity as a typical pathological feature.