COX-2 induction in mice with experimental nutritional steatohepatitis: Role as pro-inflammatory mediator.
The underlying mechanisms that perpetuate liver inflammation in nonalcoholic steatohepatitis are poorly understood. We explored the hypothesis that cyclooxygenase-2 (COX-2) can exert pro-inflammatory effects in metabolic forms of fatty liver disease. Male wild-type (WT) C57BL6/N or peroxisome proliferator-activated receptor alpha knockout (PPAR-alpha-/-) mice were fed a lipogenic, methionine- and choline-deficient (MCD) diet or the same diet with supplementary methionine and choline (control). COX-2 was not expressed in livers of mice fed the control diet. In mice fed the MCD diet, hepatic expression of COX-2 messenger RNA and protein occurred from day 5, continued to rise, and was 10-fold higher than controls after 5 weeks, thereby paralleling the development of steatohepatitis. Upregulation of COX-2 was even more pronounced in PPAR-alpha-/- mice. Induction of COX-2 was completely prevented by dietary supplementation with the potent PPAR-alpha agonist Wy-14,643 in WT but not PPAR-alpha-/- mice. COX-2 upregulation was preceded by activation of nuclear factor kappaB (NF-kappaB) and coincided with increased levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, and intercellular adhesion molecule 1 (ICAM-1). Selective COX-2 inhibitors (celecoxib and NS-398) protected against the development of steatohepatitis in WT but not PPAR-alpha-/- mice. In conclusion, induction of COX-2 occurs in association with NF-kappaB activation and upregulation of TNF-alpha, IL-6, and ICAM-1 in MCD diet-induced steatohepatitis. PPAR-alpha suppresses both COX-2 and development of steatohepatitis, while pharmacological inhibition of COX-2 activity ameliorates the severity of experimental steatohepatitis. COX-2 may therefore be a pro-inflammatory mediator in metabolic forms of steatohepatitis.
Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia.
Jun
J
Yu
Emilia
E
Ip
Aileen
A
Dela Peña
Jing Yun
JY
Hou
Jayshree
J
Sesha
Natasha
N
Pera
Pauline
P
Hall
Richard
R
Kirsch
Isabelle
I
Leclercq
Geoffrey C
GC
Farrell
D000818:Animals; D002796:Choline Deficiency; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004032:Diet; D004790:Enzyme Induction; D005234:Fatty Liver / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D050155:Lipogenesis; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D047493:PPAR alpha / Q000172:deficiency / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D018836:Inflammation Mediators; D015850:Interleukin-6; D016328:NF-kappa B; D047493:PPAR alpha; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D008715:Methionine; D051546:Cyclooxygenase 2