Abstract
Arachidonic acid (AA) signaling pathway is an important constituent of inflammatory processes. In our previous study, it was found that dihydro-stilbene gigantol relieved hepatic inflammation in mice with CCl4-induced acute liver injury. This study aimed to investigate the involvement of arachidonate metabolic cascade in this process. Our results showed CCl4 activated AA metabolism with the evidence of cPLA2 phosphorylation, which was dependent on the MAPK/JNK activation. Pretreatment with JNK inhibitor SU3327 or gigantol abolished the cPLA2 activation, along with the attenuation of liver damage. Besides, gigantol markedly decreased immune cells activation. Metabolomic analysis revealed that gigantol universally reversed the upregulation of major AA metabolites in injured mouse livers induced by CCl4, especially 12-hydroxyeicosatetraenoic acid (12-HETE). Gigantol also decreased the mRNA and protein expression of platelet-, and leukocyte-type 12-lipoxxygenase (LOX) in the liver. Furthermore, pan-LOX inhibitor nordihydroguaiaretic acid (NDGA) and specific 12-LOX inhibitors baicalein and ML351 attenuated the liver injury to the same extent as gigantol. Overall, our study elucidated a comprehensive profile of AA metabolites during hepatic inflammation caused by CCl4, highlighting the role of 12-LOX-12-HETE pathway in this process. And gigantol alleviated liver inflammation partly through inhibiting the JNK/cPLA2/12-LOX pathway.
Highlights
Inflammatory response is the common pathology of various liver diseases, despite the different etiologies
We utilized the CCl4-induced mice liver injury model and the probe drug gigantol to investigate the mechanistic link between the arachidonate metabolic cascade and hepatic inflammation
The inflammatory responses caused by C Cl4 were accompanied with the activation of MAPK/JNK, cytosolic phospholipase A2 (cPLA2) and immune cells, which were all reversed by gigantol
Summary
Inflammatory response is the common pathology of various liver diseases, despite the different etiologies. The free AA in cells can be metabolized by non-enzymatic pathway and three enzymatic pathways, including lipoxygenases (LOX), cytochrome P450 enzymes (CYP450) and cyclooxygenase (COX) pathways. These metabolic pathways will transform AA into a series of oxidized metabolites collectively described as e icosanoids[1]. This study aimed to further investigate the role of different arachidonate metabolic cascades in the pathogenesis of C Cl4-induced hepatotoxicity and to explore potential intervention strategies. Our previous study showed that dihydro-stilbene gigantol had great anti-inflammatory effects both in vitro and in vivo. It alleviated the C Cl4-induced liver inflammation in mice. The elucidation of the AA metabolites profile and key signaling pathways during liver inflammation will provide clues for developing new therapeutics to treat acute liver injury
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