Ferulic acid ameliorates acetaminophen‐induced acute liver injury by promoting AMPK‐mediated protective autophagy

Abstract

Acetaminophen (APAP), one of the most widely used antipyretics and analgesics, principally results in acute liver injury (ALI) in developed countries when taken overdose. Ferulic acid (FA) is a natural polyphenol compound existing in many plants that has free radical scavenging, anti-inflammatory, and liverprotective properties. However, the effect and underlying mechanism of FA in treating APAP-induced ALI have not been fully elucidated. Herein, we established a mouse model of APAP-induced ALI and used APAP-stimulated MPHs for biochemical assessment of molecular parameters. After constructing networks and obtaining predicted targets from public databases, we further verified the putative pathways using immune-blotting assays both in vivo and in vitro. The reign of liver necrosis, serum levels of ALT and AST, and oxidative stress in livers significantly elevated after APAP treatment, which were almost recovered back to normal levels by FA administration. In addition, FA significantly upregulated the APAP-induced downregulation of hepatic specific markers, including HNF4a, Foxa2, and ALB. Then, the results of functional enrichment indicated the possible signaling pathways of FA against APAP challenge, mainly including AMPK, autophagy, apoptosis, and other metabolic process. Furthermore, FA markedly reversed the APAP-induced decline of mitochondria membrane potential, increased ratio of BAX/BCL2 and CASPASE 3 expression, and promoted autophagy flux of hepatocytes by upregulating AMPK phosphorylation, which were abrogated by a specific AMPK inhibitor, compound C. Overall, the hepatoprotective effect of FA on APAP-induced ALI might be associated with anti-oxidant and anti-apoptosis, which were at least partly attributed to AMPK-mediated protective autophagy.

Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis

“…However, caloric restriction resulted in an AMPK-regulated increase in catabolic processes, such as the turnover of mitochondria. AMPK activation and mitophagy are well-established to reduce the severity of APAP-induced mitochondrial damage due to lower ROS levels [58][59][60][61][62]. Paradoxically, starvation may therefore have a similar effect than glucose administration, i.e., it reduces the impact of mitochondria-dependent cellular energy production and ROS formation during APAP intoxication.…”

Molecular mechanism and research progress on pharmacology of ferulic acid in liver diseases

“…In another study, an APAP-induced acute liver injury (ALI) mouse model was established. It was found that APAP treatment could lead to liver necrosis ( Wu et al, 2022 ). APAP can cause a significant increase in serum ALT, AST and oxidative stress.…”

“…FA further inhibited APAP-induced hepatocyte apoptosis by increasing Bcl-2 and decreasing caspase-3 and Bax protein levels. The results of functional enrichment suggest that FA is involved in the regulation of the mitogen-activated protein kinase (MAPK) signalling pathway and other metabolic processes ( Wu et al, 2022 ).…”

Natural-Product-Mediated Autophagy in the Treatment of Various Liver Diseases

“…Furthermore, ferulic acid (FA) isolated from multiple herbs was also reported to ameliorate APAP-induced ALI by promoting the AMPK-mediated protective autophagy. The addition of AMPK inhibitor compound c abolished FA-induced up-regulation of autophagy activation-associated proteins such as LC3, ATG5 and eventually the hepatoprotective activity of FA [ 137 ]. From a different perspective, a researcher found that APAP could induce harmful overactivation of autophagy, which could be rectified by alpha-mangostin (α-MG) derived from Garcinia mangostana by activating the AKT-mTOR pathway.…”