Ferulic acid alleviates lipotoxicity-induced hepatocellular death through the SIRT1-regulated autophagy pathway and independently of AMPK and Akt in AML-12 hepatocytes

Background: Lipotoxicity-induced cell death plays a detrimental role in the pathogenesis of metabolic diseases. Ferulic acid, widespread in plant-based food, is a radical scavenger with multiple bioactivities. However, the benefits of ferulic acid against hepatic lipotoxicity are largely unclear. Here, we investigated the protective effect of ferulic acid against palmitate-induced lipotoxicity and clarified its potential mechanisms in AML-12 hepatocytes.

Methods: AML-12 mouse hepatocytes were exposed to palmitate to mimic lipotoxicity. Different doses (25, 50, and 100 μM) of ferulic acid were added 2 h before palmitate treatment. Cell viability was detected by measuring lactate dehydrogenase release, nuclear staining, and the expression of cleaved-caspase-3. Intracellular reactive oxygen species content and mitochondrial membrane potential were analysed by fluorescent probes. The potential mechanisms were explored by molecular biological methods, including Western blotting and quantitative real-time PCR, and were further verified by siRNA interference.

Results: Our data showed that ferulic acid significantly inhibited palmitate-induced cell death, rescued mitochondrial membrane potential, reduced reactive oxygen species accumulation, and decreased inflammatory factor activation, including IL-6 and IL-1beta. Ferulic acid significantly stimulated autophagy in hepatocytes, whereas autophagy suppression blocked the protective effect of ferulic acid against lipotoxicity. Ferulic acid-activated autophagy, which was triggered by SIRT1 upregulation, was mechanistically involved in its anti-lipotoxicity effects. SIRT1 silencing blocked most beneficial changes induced by ferulic acid.

Conclusions: We demonstrated that the phytochemical ferulic acid, which is found in plant-based food, protected against hepatic lipotoxicity, through the SIRT1/autophagy pathway. Increased intake of ferulic acid-enriched food is a potential strategy to prevent and/or improve metabolic diseases with lipotoxicity as a typical pathological feature.