Tsujimoto Shunsuke, Kishina Manabu, Koda Masahiko, Yamamoto Yasutaka, Tanaka Kohei, Harada Yusuke, Yoshida Akio, Hisatome Ichiro
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.
Int J Mol Med. 2016 Sep;38(3):721-8. doi: 10.3892/ijmm.2016.2674. Epub 2016 Jul 11.
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.
环氧化酶（COX）-2选择性抑制剂可抑制非酒精性脂肪性肝病（NAFLD）；然而，其确切作用机制尚不清楚。本研究的目的是探讨COX-2选择性抑制剂尼美舒利在高脂饮食（HFD）诱导的肥胖小鼠模型中如何抑制NAFLD。将小鼠分为正常饲料组（NC）、HFD组或HFD加尼美舒利组（HFD-nime），喂养12周。HFD组小鼠体重、肝脏COX-2 mRNA表达和甘油三酯蓄积显著增加。HFD-nime组甘油三酯蓄积受到抑制。HFD组肝脏过氧化物酶体增殖物激活受体γ（PPARγ）和天然PPARγ激动剂15-脱氧-Δ12,14-前列腺素J2（15d-PGJ2）的mRNA表达显著增加，而HFD-nime组则显著受到抑制。与NC组相比，HFD组葡萄糖代谢受损，而HFD-nime组葡萄糖代谢显著改善。此外，与NC组相比，HFD组血浆胰岛素水平升高，而HFD-nime组血浆胰岛素水平降低。这些结果表明，HFD诱导的NAFLD是由肝脏COX-2表达增加介导的。我们认为，由COX-2介导的15d-PGJ2的产生通过激活PPARγ诱导NAFLD和肝脏胰岛素抵抗。此外，与NC组相比，HFD组金属蛋白酶组织抑制剂-1（TIMP-1）、前胶原-1和单核细胞趋化蛋白-1（MCP-1）的mRNA表达以及F4/80阳性肝（枯否）细胞数量显著增加，而尼美舒利可使其减少。总之，COX-2可能成为预防饮食相关肥胖中NAFLD和胰岛素抵抗发展的分子靶点。
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