title: Nimesulide, a cyclooxygenase-2 selective inhibitor, suppresses obesity-related non-alcoholic fatty liver disease and hepatic insulin resistance through the regulation of peroxisome proliferator-activated receptor γ.
abstract: Cyclooxygenase (COX)-2 selective inhibitors suppress non-alcoholic fatty liver disease (NAFLD); however, the precise mechanism of action remains unknown. The aim of this study was to examine how the COX-2 selective inhibitor nimesulide suppresses NAFLD in a murine model of high-fat diet (HFD)‑induced obesity. Mice were fed either a normal chow diet (NC), an HFD, or HFD plus nimesulide (HFD-nime) for 12 weeks. Body weight, hepatic COX-2 mRNA expression and triglyceride accumulation were significantly increased in the HFD group. Triglyceride accumulation was suppressed in the HFD-nime group. The mRNA expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ) and the natural PPARγ agonist 15-deoxy-Δ12,14-prostaglandin J2 (15d‑PGJ2) were significantly increased in the HFD group and significantly suppressed in the HFD-nime group. Glucose metabolism was impaired in the HFD group compared with the NC group, and it was significantly improved in the HFD-nime group. In addition, the plasma insulin levels in the HFD group were increased compared with those in the NC group, and were decreased in the HFD-nime group. These results indicate that HFD-induced NAFLD is mediated by the increased hepatic expression of COX-2. We suggest that the production of 15d-PGJ2, which is mediated by COX-2, induces NAFLD and hepatic insulin resistance by activating PPARγ. Furthermore, the mRNA expression of tissue inhibitor of metalloproteinases-1 (TIMP‑1), procollagen-1 and monocyte chemoattractant protein-1 (MCP-1), as well as the number of F4/80-positive hepatic (Kupffer) cells, were significantly increased in the HFD group compared with the NC group, and they were reduced by nimesulide. In conclusion, COX-2 may emerge as a molecular target for preventing the development of NAFLD and insulin resistance in diet-related obesity.
authors.affiliation: Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, Yonago, Tottori 683-8504, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Tsujimoto
authors.affiliation: Second Department of Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kishina
authors.affiliation: Second Department of Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koda
authors.affiliation: Pharmaceutical Research Group II, Pharmacology Research Department, Pharmaceutical Development Research Laboratories, Tokyo 191‑8512, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, Yonago, Tottori 683-8504, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, Yonago, Tottori 683-8504, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Harada
authors.affiliation: Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, Yonago, Tottori 683-8504, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, Yonago, Tottori 683-8504, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000517:prevention & control*; D009765:Obesity / Q000150:complications* / Q000209:etiology; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: C477819:15-deoxyprostaglandin J2; D018932:Chemokine CCL2; D024042:Collagen Type I; D052246:Cyclooxygenase 2 Inhibitors; D007328:Insulin; D047495:PPAR gamma; D013449:Sulfonamides; D019715:Tissue Inhibitor of Metalloproteinase-1; D014280:Triglycerides; D051546:Cyclooxygenase 2; D005947:Glucose; D015230:Prostaglandin D2; C012655:nimesulide