Fenofibrate, a peroxisome proliferator-activated receptor alpha-agonist, blocks lipopolysaccharide-induced inflammatory pathways in mouse liver.
10.14701/kjhbps.2013.17.3.89
- Author:
Tae Wan WON
1
Author Information
1. Department of Surgery, School of Medicine, Wonkwang University, Iksan, Korea. furufuru79@naver.com
- Publication Type:Original Article
- Keywords:
Peroxisome proliferator activated receptors alpha agonist
- MeSH:
Animals;
Bile;
Carcinoma, Hepatocellular;
Cell Proliferation;
Clinical Protocols;
Cytokines;
Fenofibrate;
Glucose;
Hep G2 Cells;
Homeostasis;
Humans;
Inflammation;
Interleukin-1beta;
Interleukin-6;
Lipid Metabolism;
Lipoproteins;
Liver;
Mice;
Mice, Knockout;
NF-kappa B;
Peroxisome Proliferator-Activated Receptors;
Peroxisomes;
PPAR alpha;
PPAR-beta;
PPAR delta;
PPAR gamma;
RNA, Messenger;
Tumor Necrosis Factor-alpha
- From:Korean Journal of Hepato-Biliary-Pancreatic Surgery
2013;17(3):89-108
- CountryRepublic of Korea
- Language:English
-
Abstract:
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: PPARalpha, beta/delta, and gamma) regulate fatty acid metabolism, glucose homeostasis, cell proliferation, differentiation and inflammation. Proinflammatory profiles including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), 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-alpha, IL-1beta, and IL-6. LPS-induced inflammation decrease the expression of peroxisome proliferator-activated receptor alpha (PPARalpha), PPARbeta/delta, PPARgamma, and coactivators PPARgamma co-activator 1 alpha (PGC-1alpha), PGC-1beta messenger RNA (mRNA) in the liver of Balb/c mouse. In addition, LPS-induced inflammation diminishes the protein level of PPARalpha, PPARbeta/delta, and PPARgamma. Proinflammatory cytokines including TNFalpha, IL-1beta, and IL-6 are the principal reducer of PPARs. However, the knockout mouse model against TNFalpha 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-alpha, IL-1beta, 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 IkappaB. Moreover, activation of PPARs abrogated LPS-induced degradation of IkappaB, thus suppressing LPS-induced NF-kappaB activities. CONCLUSIONS: Therefore, fenofibrate decreases the expression and secretion of TNF-alpha, IL-1beta, and IL-6 via the NF-kappaB signaling pathway, thus serving as therapeutic targets to attenuate inflammation that is involved in hepatic pathological progression.
