PMID- 27431935 OWN - NLM STAT- MEDLINE DCOM- 20170321 LR - 20181113 IS - 1791-244X (Electronic) IS - 1107-3756 (Print) IS - 1107-3756 (Linking) VI - 38 IP - 3 DP - 2016 Sep TI - 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 gamma. PG - 721-8 LID - 10.3892/ijmm.2016.2674 [doi] AB - 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 gamma (PPARgamma) and the natural PPARgamma agonist 15-deoxy-Delta12,14-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 PPARgamma. 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. FAU - Tsujimoto, Shunsuke AU - Tsujimoto S AD - 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. FAU - Kishina, Manabu AU - Kishina M AD - Second Department of Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan. FAU - Koda, Masahiko AU - Koda M AD - Second Department of Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan. FAU - Yamamoto, Yasutaka AU - Yamamoto Y AD - Pharmaceutical Research Group II, Pharmacology Research Department, Pharmaceutical Development Research Laboratories, Tokyo 191‑8512, Japan. FAU - Tanaka, Kohei AU - Tanaka K AD - 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. FAU - Harada, Yusuke AU - Harada Y AD - 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. FAU - Yoshida, Akio AU - Yoshida A AD - 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. FAU - Hisatome, Ichiro AU - Hisatome I AD - 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. LA - eng PT - Journal Article DEP - 20160711 PL - Greece TA - Int J Mol Med JT - International journal of molecular medicine JID - 9810955 RN - 0 (15-deoxyprostaglandin J2) RN - 0 (Chemokine CCL2) RN - 0 (Collagen Type I) RN - 0 (Cyclooxygenase 2 Inhibitors) RN - 0 (Insulin) RN - 0 (PPAR gamma) RN - 0 (Sulfonamides) RN - 0 (Tissue Inhibitor of Metalloproteinase-1) RN - 0 (Triglycerides) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - IY9XDZ35W2 (Glucose) RN - RXY07S6CZ2 (Prostaglandin D2) RN - V4TKW1454M (nimesulide) SB - IM MH - Animals MH - Chemokine CCL2/genetics/metabolism MH - Collagen Type I/genetics/metabolism MH - Cyclooxygenase 2/genetics/metabolism MH - Cyclooxygenase 2 Inhibitors/pharmacology MH - Diet, High-Fat/adverse effects MH - Gene Expression/drug effects MH - Glucose/metabolism MH - Immunohistochemistry MH - Insulin/blood MH - *Insulin Resistance MH - Kupffer Cells/drug effects/metabolism MH - Liver/*drug effects/metabolism/physiopathology MH - Male MH - Mice, Inbred C57BL MH - Non-alcoholic Fatty Liver Disease/complications/*prevention & control MH - Obesity/*complications/etiology MH - PPAR gamma/agonists/*genetics/metabolism MH - Prostaglandin D2/analogs & derivatives/metabolism/pharmacology MH - Reverse Transcriptase Polymerase Chain Reaction MH - Sulfonamides/*pharmacology MH - Tissue Inhibitor of Metalloproteinase-1/genetics/metabolism MH - Triglycerides/metabolism PMC - PMC4990319 EDAT- 2016/07/20 06:00 MHDA- 2017/03/23 06:00 PMCR- 2016/07/11 CRDT- 2016/07/20 06:00 PHST- 2016/03/22 00:00 [received] PHST- 2016/06/30 00:00 [accepted] PHST- 2016/07/20 06:00 [entrez] PHST- 2016/07/20 06:00 [pubmed] PHST- 2017/03/23 06:00 [medline] PHST- 2016/07/11 00:00 [pmc-release] AID - ijmm-38-03-0721 [pii] AID - 10.3892/ijmm.2016.2674 [doi] PST - ppublish SO - Int J Mol Med. 2016 Sep;38(3):721-8. doi: 10.3892/ijmm.2016.2674. Epub 2016 Jul 11.