Ferulic acid alleviates lipotoxicity-induced hepatocellular death through the SIRT1-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 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.

Effects of Dietary Ferulic Acid Supplementation on Hepatic Injuries in Tianfu Broilers Challenged with Lipopolysaccharide

“…FA can reduce apoptosis through increasing the ratio of Bcl-2/Bax [ 30 ]. Furthermore, a recent study indicates that FA shows significant protective effects during cellular or tissue damage [ 31 ]. However, the information of the clinical effects of FA supplementation in LPS-induced hepatic injury chickens is limited.…”

Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy

“…Ferulic acid has shown remarkable anti-inflammatory and antioxidant activity in pre-clinical studies and, as sodium ferulate, is widely used in cardiovascular medicine in China [90,91]. Recent studies have found that this may reflect, in large part, the ability of ferulic acid to up-regulate SIRT1 expression at the mRNA and protein level [92][93][94][95][96][97]. This effect has been demonstrated in a number of cell types, and hence appears to be a general effect; its mechanistic basis remains unclear.…”

Recent Advances in Biological Activity, New Formulations and Prodrugs of Ferulic Acid

“…Moreover, the oral administration of ferulic acid to rats fed with a high-fat diet alleviated development of non-alcoholic fatty liver disease (NAFLD) by reducing the deposition of triglycerides and cholesterol in the liver [ 37 ]. The compound protects AML-12 hepatocytes against palmitate-induced lipotoxicity by reducing ROS (reactive oxygen species) accumulation and decreasing activation of proinflammatory cytokines, i.e., IL-6 and IL-1β [ 38 ]. Therefore, the development of new forms of functional foods enriched with ferulic acid is reasonable in the case of metabolic diseases.…”