Abstract
10‐Hydroxy‐trans‐2‐decenoic acid (10H2DA) is a unique lipid component of royal jelly produced by worker honeybees that exerts insulin‐like effects. We herein investigated the effects of 10H2DA on the gene expression of aquaporin 9 (AQP9), which functions as a glycerol transporter in the liver, to clarify whether 10H2DA modulates energy metabolism. 10H2DA suppressed AQP9 gene expression in HepG2 cells by promoting the phosphorylation of Akt and AMP‐activated protein kinase (AMPK). This suppression was partially recovered by the treatment of cells with inhibitors for Akt and AMPK. Based on the result showing that leptomycin B partially recovered the suppression of AQP9 gene expression, 10H2DA inhibited the expression of Foxa2, a transcription factor for the AQP9 gene, and also induced its nuclear exclusion. Although 10H2DA up‐regulated phosphoenolpyruvate carboxykinase and glucose‐6‐phosphatase gene expression, this was suppressed through the modulation of Foxa2 by insulin. These results suggest that 10H2DA suppresses AQP9 gene expression through the phosphorylation of Akt and AMPK and down‐regulation of Foxa2 expression.
Highlights
Aquaporin 9 (AQP9), which belongs to the aquaglyceroporin family including AQP3, 7, and 10, is mainly expressed in the human liver, brain, testis, and white blood cells, and functions as a unique glycerol channel in the liver (Calamita et al, 2012; Tsukaguchi et al, 1998; Tsukaguchi, Weremowicz, Morton, & Hediger, 1999)
When HepG2 cells were treated with 2 mM 10‐Hydroxy‐trans‐2‐decenoic acid (10H2DA) in the presence of this inhibitor, aquaporin 9 (AQP9) mRNA expression levels were similar to those of the control
These expression levels were lower than those without 10H2DA. These results suggest that 10H2DA induces the nuclear exclusion of forkhead box a2 (Foxa2) and suppression of Foxa2 expression
Summary
Aquaporin 9 (AQP9), which belongs to the aquaglyceroporin family including AQP3, 7, and 10, is mainly expressed in the human liver, brain, testis, and white blood cells, and functions as a unique glycerol channel in the liver (Calamita et al, 2012; Tsukaguchi et al, 1998; Tsukaguchi, Weremowicz, Morton, & Hediger, 1999). AQP3, 7, and 9 gene expression was previously reported to be suppressed by insulin through the activation of Akt (Kishida et al, 2001; Kuriyama et al, 2002). The activation of AMPK by 5‐aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribonucleoside (AICAR) was previously shown to suppress AQP9 expression via the phosphorylation of Akt followed by the phosphorylation and nuclear exclusion of Foxa (Yokoyama et al, 2011). Previous studies reported that royal jelly exhibited insulin‐like activity as a hypoglycemic effect (Münstedt, Bargello, & Hauenschild, 2009; Nomura et al, 2007; Zamami et al, 2008). We initially investigated whether 10H2DA affected AQP9 mRNA expression because AQP9 is permeable to glycerol in the liver and glycerol is a source material for glyco‐ and lipid metabolism. We elucidated the mechanisms by which 10H2DA inhibits AQP9 mRNA expression
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