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

Tsujimoto,Shunsuke; Kishina,Manabu; Koda,Masahiko; Yamamoto,Yasutaka; Tanaka,Kohei; Harada,Yusuke; Yoshida,Akio; Hisatome,Ichiro

doi:10.3892/ijmm.2016.2674

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

Authors:
- Shunsuke Tsujimoto
- Manabu Kishina
- Masahiko Koda
- Yasutaka Yamamoto
- Kohei Tanaka
- Yusuke Harada
- Akio Yoshida
- Ichiro Hisatome
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Affiliations: 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, Second Department of Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan, Pharmaceutical Research Group II, Pharmacology Research Department, Pharmaceutical Development Research Laboratories, Tokyo 191‑8512, Japan
Published online on: July 11, 2016 https://doi.org/10.3892/ijmm.2016.2674
Pages: 721-728
Copyright: © Tsujimoto et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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