OP-9：AICAR down regulates the expression of insulin receptor in HepG2 cells.

Kazuya Matsumoto, Kazuhiko Nakamaru, Tetsuya Taguchi, Mihoshi Suefuji, Junji Kawashima, Hiroyuki Motoshima, Kaku Tsuruzoe, and Eiichi Araki

Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan,

Aim: The expression of insulin receptor is regulated with hormones or cell differentiations in tissue-specific manner. Liver is one of the major target organs of insulin action, and also is the target of anti-diabetic agent, biguanide compound.   Recently, biguanide has been reported to ameliorate insulin resistance via activation of AMPK in liver. In this study, we investigated the effects of AICAR, an activator of AMPK, on the expression of insulin receptor in HepG2 cells.  

Methods & Results: The insulin receptor protein expression was decreased in cells treated with AICAR for 48 hours in a dose-dependent manner, concomitant with a decrease of the insulin receptor mRNA expression. Luciferase reporter gene assay revealed that the transcriptional activity of the human insulin receptor gene promoter was down regulated with AICAR treatment. Cis-elements responsible for the AICAR-induced suppression existed within 0.6 kb upstream from the ATG codon in the insulin receptor gene. Five putative insulin response elements (IRE) exist in the upstream of human insulin receptor gene promoter、and tow of them are located in the 0.6 kb region. Nuclear protein(s) that bound to the IREs were suggested to be Foxo1 with electrophoretic mobility shift assays.   Over-expression of Foxo1 increased transcription activity of the 0.6 kb fragment of insulin receptor gene promoter in HepG2.   Bindings of Foxo1 to the IREs were decreased with AICAR-treatment in a dose-dependent manner.  

Conclusion: These findings suggested that AICAR down regulates the expression of human insulin receptor. The decrease of the insulin receptor expression may partly through the suppression of Foxo1-IRE binding.   

(295 words <300)

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