Key result
Fenofibrate pretreatment reduces TNF-α, IL-1β, and IL-6 via NF-κB signaling in mouse liver inflammation.
Why the study?
Inflammatory responses during the acute phase alter lipid metabolism and decrease PPAR expression, but the mechanisms and potential interventions remain unclear.
Does fenofibrate reduce LPS-induced inflammatory cytokine production in mouse liver and human hepatoma cells?
Does fenofibrate reduce LPS-induced inflammatory cytokine production in mouse liver and human hepatoma cells?
Fenofibrate attenuates LPS-induced hepatic inflammation by decreasing proinflammatory cytokines via the NF-κB signaling pathway in preclinical models.
May warrant exploration of fenofibrate for inflammatory liver conditions; leaves open translation from animal models to clinical practice.
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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Tae Wan Won (2013) studied LPS-induced hepatic inflammation. Fenofibrate vs. Vehicle (methylcellulose) + LPS was evaluated on Proinflammatory cytokine (TNF-α, IL-1β, IL-6) production and PPAR expression. Fenofibrate pretreatment decreased the expression and secretion of TNF-α, IL-1β, and IL-6 via the NF-κB signaling pathway in a mouse model of LPS-induced liver inflammation.
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