Obesity (Silver Spring). 2013;21:E22-E25.
A retinoic acid receptor agonist tamibarotene suppresses iron accumulation in the liver.
Yoshikawa O, Ebata Y, Tsuchiya H, Kawahara A, Kojima C, Ikeda Y, Hama S, Kogure K, Shudo K, Shiota G.
Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan.
Objective: Hepatic iron overload (HIO) and iron-induced oxidative stress have recently emerged as an important factor for the development and progression of insulin resistance. The aim of this study was to evaluate the effect of tamibarotene, a selective retinoic acid receptor α/β agonist, on hepatic iron metabolism, based on our previous findings that retinoids suppress hepatic iron accumulation by increasing hepatic iron efflux through the regulation of hemojuvelin and ferroportin expression.
Design and Methods: We quantitated the non-heme iron content and iron metabolism-related gene expression in the liver, and serum lipid and blood glucose levels in KK-Ay mice after dietary administration of tamibarotene.
Results: It was demonstrated that tamibarotene significantly reduced blood glucose and hepatic iron, but not serum lipids, and that hemojuvelin expression significantly decreased while ferroportin increased, as observed previously.
Conclusions: These results suggest that tamibarotene is a promising alternative for the treatment of insulin resistance associated with HIO.
We have so far investigated the pathophysiological roles of retinoic acid receptor (RAR) in the liver.
Oxidative stress induced by hepatic iron overload has emerged as an important factor for disease progression in patients with chronic hepatitis C, alcoholic liver disease, and non-alcoholic steatohepatitis. We found that retinoids, all-trans-retinoic acid (ATRA) and acyclic retinoid (pretinoin) reduce hepatic iron content through the transcriptional regulation of hemojuvelin (Gastroenterology. 136, 341-350, 2009). This represents, until now, an unrecognized retinoid function that prevents iron-induced oxidative stress in the liver. Moreover, taking advantage of a mouse model of non-alcoholic fatty liver disease, we found that RAR agonists, ATRA and tamibarotene, efficiently ameliorate insulin resistance in a leptin-dependent manner (Hepatology. 56,1319-1330, 2012).
These findings prompted us to further investigate the effect of tamibarotene on hepatic iron metabolism. As expected, tamibarotene significantly suppressed an age-dependent increase in blood glucose levels of KK-Ay mice, in association with the decrease in hepatic iron content and hemojuvelin expression.
Our findings suggest that RAR agonists might have potential for treating chronic liver disease associated with hepatic iron overload and insulin resistance (Figure).