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.

Diosgenin prevents high-fat diet-induced rat non-alcoholic fatty liver disease through the AMPK and LXR signaling pathways

“…High glucose concentration is associated with insulin resistance, which leads to elevated hepatic glucose production, hyperglycemia and hyperlipidemia (24). exposure of HepG2 cells to high concentrations of glucose inhibits the phosphorylation of amPK and acc (25).…”

Arachidonic Acid Metabolites in Cardiovascular and Metabolic Diseases

“…Interestingly, PGE2 promotes lipogenesis and inhibits tissue growth factor beta 1 (TGFβ1)-mediated collagen production by activated stellate cells, suggesting an anti-fibrotic function of PGE2 [ 179 ]. Additionally, the COX pathway is involved in the pathogenesis of NAFLD through its effects on PPARγ, which is implicated in insulin resistance and hepatic steatosis [ 180 ].…”

Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model

“…Both in vivo and in vitro evidence suggest that prostaglandins might contribute to the development of steatosis. Thus, both the knockdown of type IV phospholipase A2 6 , 7 , which releases arachidonic acid for prostaglandin synthesis from phospholipids, or a selective inhibition of cyclooxygenase 2 (COX-2) 8 , the key enzyme in prostaglandin synthesis, protected against diet-induced hepatic steatosis. In addition, prostaglandin E 2 has been shown to enhance lipid accumulation in hepatocytes by an inhibition of VLDL-synthesis and β-oxidation 9 – 12 .…”