Fenofibrate, a peroxisome proliferator-activated receptor alpha-agonist, blocks lipopolysaccharide-induced inflammatory pathways in mouse liver
Korean Journal of Hepato-Biliary-Pancreatic Surgery
;
: 89-108, 2013.
Article
in English
| WPRIM
| ID: wpr-63501
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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Fenofibrate
/
Bile
/
RNA, Messenger
/
Clinical Protocols
/
Cytokines
/
NF-kappa B
/
Interleukin-6
/
Tumor Necrosis Factor-alpha
/
Mice, Knockout
/
Carcinoma, Hepatocellular
Type of study:
Practice guideline
/
Prognostic study
Limits:
Animals
/
Humans
Language:
English
Journal:
Korean Journal of Hepato-Biliary-Pancreatic Surgery
Year:
2013
Type:
Article
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