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COX-2 induction in mice with experimental nutritional steatohepatitis: Role as pro-inflammatory mediator.
Hepatology. 2006 Apr; 43(4):826-36.Hep

Abstract

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.

Authors+Show Affiliations

Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16557554

Citation

Yu, Jun, et al. "COX-2 Induction in Mice With Experimental Nutritional Steatohepatitis: Role as Pro-inflammatory Mediator." Hepatology (Baltimore, Md.), vol. 43, no. 4, 2006, pp. 826-36.
Yu J, Ip E, Dela Peña A, et al. COX-2 induction in mice with experimental nutritional steatohepatitis: Role as pro-inflammatory mediator. Hepatology. 2006;43(4):826-36.
Yu, J., Ip, E., Dela Peña, A., Hou, J. Y., Sesha, J., Pera, N., Hall, P., Kirsch, R., Leclercq, I., & Farrell, G. C. (2006). COX-2 induction in mice with experimental nutritional steatohepatitis: Role as pro-inflammatory mediator. Hepatology (Baltimore, Md.), 43(4), 826-36.
Yu J, et al. COX-2 Induction in Mice With Experimental Nutritional Steatohepatitis: Role as Pro-inflammatory Mediator. Hepatology. 2006;43(4):826-36. PubMed PMID: 16557554.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - COX-2 induction in mice with experimental nutritional steatohepatitis: Role as pro-inflammatory mediator. AU - Yu,Jun, AU - Ip,Emilia, AU - Dela Peña,Aileen, AU - Hou,Jing Yun, AU - Sesha,Jayshree, AU - Pera,Natasha, AU - Hall,Pauline, AU - Kirsch,Richard, AU - Leclercq,Isabelle, AU - Farrell,Geoffrey C, PY - 2006/3/25/pubmed PY - 2006/5/5/medline PY - 2006/3/25/entrez SP - 826 EP - 36 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 43 IS - 4 N2 - 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. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/16557554/COX_2_induction_in_mice_with_experimental_nutritional_steatohepatitis:_Role_as_pro_inflammatory_mediator_ L2 - https://doi.org/10.1002/hep.21108 DB - PRIME DP - Unbound Medicine ER -