Mechanisms of adiponectin-mediated COX-2 induction and protection against iron injury in mouse hepatocytes
✍ Scribed by Fei-Peng Lee; Chih-Yu Jen; Chih-Cheng Chang; Ying Chou; Heng Lin; Chih-Ming Chou; Shu-Hui Juan
- Book ID
- 102882868
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 511 KB
- Volume
- 224
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Adiponectin (APN)‐mediated cyclooxygenase (COX)‐2 induction is known to have various protective effects on cardiovascular diseases. However, the molecular mechanisms of APN‐mediated COX‐2 induction and its protection against iron‐mediated injury in hepatocytes are still unclear. Herein, we show that AMP‐mediated peroxisome proliferator‐activated receptor (PPAR)α activation was attributable to COX‐2 induction by APN, which was further confirmed by identifying novel functional PPAR responsive elements (PPREs) in the mouse COX‐2 promoter region. Prostaglandin (PG)I2 and PGE2, metabolites of COX‐2, time‐dependently increased in hepatocytes treated with APN. Interestingly, beraprost and misoprostol, respective agonists for PGI2 and PGE2, mimicked the protective effects of APN in iron‐mediated inflammation in hepatocytes. The iron dextran‐activated nuclear factor (NF)‐κB pathway was correlated with the increased production of inflammatory cytokines including tumor necrosis factor‐α, intercellular adhesion molecule‐1, and monocyte chemotactic protein‐1. This was eliminated by administration of APN, whereas blockage of PPARα activation, an upstream regulator of COX‐2 induction by APN, and COX‐2 activation reversed the anti‐inflammatory effect of APN, suggesting the crucial role of COX‐2 in this event. Herein, we demonstrate that APN‐mediated COX‐2 induction through a PPARα‐dependent mechanism, and COX‐2 exerted an anti‐inflammatory effect of APN in hepatocytes subjected to iron challenge. J. Cell. Physiol. 224: 837–847, 2010. © 2010 Wiley‐Liss, Inc.