Host: The Japanese Society of Toxicology
Chlorogenic acid (CGA), the most abundant polyphenol in coffee, has been reported to have an anti-oxidative activity and various health benefits by activating the nuclear factor-erythroid 2 related factor 2 (Nrf2). However, the mechanism underlying Nrf2 activation by CGA has not been fully elucidated. Nrf2 is mainly regulated at protein levels via proteasomal degradation orchestrated by several E3 ubiquitin ligase adaptor proteins, including Keap1 and β-TrCP, and newly identified WDR23. In order to study the mechanism behind the activation of Nrf2 and identification of its role in lifespan elongation, we used both human hepatocellular carcinoma (Hep3B) cells and nematode Caenorhabditis elegans. In the present study, we showed that treatment of Hep3B cells with CGA increased Nrf2 protein levels and transcriptional activity, leading to enhanced expression of its target genes (HO-1 and NQO1). Knockdown of WDR23, but not Keap1 or β-TrCP, diminished these effects; suggesting that CGA requires WDR23. In C. elegans, CGA increased SKN-1 (Nrf2 homolog) protein levels and the expression of its target genes (gcs-1 and gss-1), prolonged the lifespan of wild-type strain, and did not affect the lifespan of skn-1 mutant strain; indicating that lifespan extension effect of CGA requires SKN-1. The effect of CGA on lifespan was dependent on WDR23, as CGA did not affect lifespan of wdr-23 mutant strain. Taken together, these results suggested that Nrf2/SKN-1 is critical for the CGA-mediated beneficial effect. Additional efforts are needed to dissect the mechanism by which WDR23 is involved in the response to CGA treatment.
