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KMID : 0870420130170030089
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Korean Journal of Hepato-Biliary-Pancreatic Surgery
2013 Volume.17 No. 3 p.89 ~ p.108
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Fenofibrate, a peroxisome proliferator-activated receptor α-agonist, blocks lipopolysaccharide-induced inflammatory pathways in mouse liver
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Won Tae-Wan
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Abstract
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Backgrounds/Aims
During the acute phase response, cytokines induce marked alterations in lipid metabolism including an increase in serum triglyceride levels and a decrease in hepatic fatty acid oxidation, in bile acid synthesis, and in high-density lipoprotein levels.
Methods
Peroxisome proliferator-activated receptors (PPARs: PPARα, β/δ, and γ) regulate fatty acid metabolism, glucose homeostasis, cell proliferation, differentiation and inflammation. Proinflammatory profiles including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) are the important pathological factors in inflammatory responses during the pathological progression of the acute phase response. Lipopolysaccarides (LPS) induced the expression of TNF-α, IL-1β, and IL-6. LPS-induced inflammation decrease the expression of peroxisome proliferator-activated receptor α (PPARα), PPARβ/δ, PPARγ, and coactivators PPARγ co-activator 1 α (PGC-1α), PGC-1β messenger RNA (mRNA) in the liver of Balb/c mouse. In addition, LPS-induced inflammation diminishes the protein level of PPARα, PPARβ/δ, and PPARγ. Proinflammatory cytokines including TNFα, IL-1β, and IL-6 are the principal reducer of PPARs. However, the knockout mouse model against TNFα and IL-6 does not block decrease of PPARs in serum and liver. The mice were pretreated with fenofibrate at 100 mg/kg for 2 days.
Results
These treatment protocols increased the amount of PPARs mRNA in the liver. Fenofibrate inhibited LPS-induced TNF-α, IL-1β, and IL-6 production in the serum and liver. Similar results were obtained when human hepatoma HepG2 cells exposed to LPS were co-incubated with fenofibrate. LPS-treated HepG2 cells decreased expression of IκB. Moreover, activation of PPARs abrogated LPS-induced degradation of IκB, thus suppressing LPS-induced NF-κB activities.
Conclusions
Therefore, fenofibrate decreases the expression and secretion of TNF-α, IL-1β, and IL-6 via the NF-κB signaling pathway, thus serving as therapeutic targets to attenuate inflammation that is involved in hepatic pathological progression.
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KEYWORD
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Peroxisome proliferator activated receptors α agonist
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