Abstract
Dietary supplementation with the n-3 polyunsaturated fatty acids (n-3 PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to rats preconditions the liver against ischemia-reperfusion (IR) injury, with reduction of the enhanced nuclear factor-κB (NF-κB) functionality occurring in the early phase of IR injury, and recovery of IR-induced pro-inflammatory cytokine response. The aim of the present study was to test the hypothesis that liver preconditioning by n-3 PUFA is exerted through peroxisone proliferator-activated receptor α (PPAR-α) activation and interference with NF-κB activation. For this purpose we evaluated the formation of PPAR-α/NF-κBp65 complexes in relation to changes in PPAR-α activation, IκB-α phosphorylation and serum levels and expression of interleukin (IL)-1β and tumor necrosis factor (TNF)-α in a model of hepatic IR-injury (1 h of ischemia and 20 h of reperfusion) or sham laparotomy (controls) in male Sprague Dawley rats. Animals were previously supplemented for 7 days with encapsulated fish oil (General Nutrition Corp., Pittsburg, PA) or isovolumetric amounts of saline (controls). Normalization of IR-altered parameters of liver injury (serum transaminases and liver morphology) was achieved by dietary n-3 PUFA supplementation. EPA and DHA suppression of the early IR-induced NF-κB activation was paralleled by generation of PPAR-α/NF-κBp65 complexes, in concomitance with normalization of the IR-induced IκB-α phosphorylation. PPAR-α activation by n-3 PUFA was evidenced by enhancement in the expression of the PPAR-α-regulated Acyl-CoA oxidase (Acox) and Carnitine-Palmitoyl-CoA transferase I (CPT-I) genes. Consistent with these findings, normalization of IR-induced expression and serum levels of NF-κB-controlled cytokines IL-lβ and TNF-α was observed at 20 h of reperfusion. Taken together, these findings point to an antagonistic effect of PPAR-α on NF-κB-controlled transcription of pro-inflammatory mediators. This effect is associated with the formation of PPAR-α/NF-κBp65 complexes and enhanced cytosolic IκB-α stability, as major preconditioning mechanisms induced by n-3 PUFA supplementation against IR liver injury.
Highlights
Human liver resections involving vascular occlusion to reduce blood loss may lead to severe hepatic dysfunction, with irreversible organ damage due to hepatocyte and endothelial cell death [1]
At 3 h of reperfusion, nuclear factor-kB (NF-kB) DNA binding activity in control rats subjected to IR was increased by 100% (p,0.05) in relation to that in sham-operated controls, an effect that was suppressed by eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) supplementation, without significant changes in sham-operated animals (Figure 2A and 2B), confirming our previous studies [3]
In agreement with previous reports, data presented in this study indicate that liver IR injury induced by 1 h of warm ischemia and up to 20 h of reperfusion is accompanied by an early (3 h) enhancement in liver NF-kB DNA binding, with up-regulation of the NF-kB signalling pathway and pro-inflammatory cytokine expression (20 h) [3,11,20], and concomitant enhanced serum levels of these NF-kB-dependent pro-inflammatory products [3]
Summary
Human liver resections involving vascular occlusion to reduce blood loss may lead to severe hepatic dysfunction, with irreversible organ damage due to hepatocyte and endothelial cell death [1]. Taking into account that vascular occlusion of the liver or ischemia (I), followed by its restoration during reperfusion (R) occurs during surgical manoeuvres such as transplantation, tissue resection under inflow occlusion (Pringle manoeuvre), and hypoperfusion shock, several preconditioning strategies affording resistance to liver IR injury have been evaluated [2] In this respect, we have established that dietary supplementation with the n-3 polyunsaturated fatty acids (n-3 PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are highly concentrated in fish oils, affords significant prevention of liver injury induced by IR in the rat, representing a novel preconditioning strategy [3]. Studies in experimental models of liver injury have reported beneficial actions of n-3 PUFA-derived resolvins and protectins, preventing liver DNA damage and oxidative stress, with significant reduction in necroinflammatory liver injury and hepatic steatosis [6,7] These mediators might explain many of the antiinflammatory actions of n-3 fatty acids, eicosanoid-independent actions including EPA and DHA effects on transcription factors regulating inflammatory gene expression such as NF-kB, should be considered. Supporting this view are the data showing the decreasing effect of n-3 PUFAs on the production of proinflammatory cytokines regulated by NF-kB [8]
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