Investigation of salicylate hepatic responses in comparison with chemical analogues of the drug

Amy R Cameron, Lisa Logie, Kashyap Patel, Sandra Bacon, Calum Forteath, Jean Harthill, Adam Roberts, Calum Sutherland, Derek Stewart, Benoit Viollet, Kei Sakamoto, Gordon J McDougall, Marc Foretz, Graham Rena

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    Abstract

    Anti-hyperglycaemic effects of the hydroxybenzoic acid salicylate might stem from effects of the drug on mitochondrial uncoupling, activation of AMP-activated protein kinase, and inhibition of NF-κB signalling. Here, we have gauged the contribution of these effects to control of hepatocyte glucose production, comparing salicylate with inactive hydroxybenzoic acid analogues of the drug. In rat H4IIE hepatoma cells, salicylate was the only drug tested that activated AMPK. Salicylate also reduced mTOR signalling, but this property was observed widely among the analogues. In a sub-panel of analogues, salicylate alone reduced promoter activity of the key gluconeogenic enzyme glucose 6-phosphatase and suppressed basal glucose production in mouse primary hepatocytes. Both salicylate and 2,6 dihydroxybenzoic acid suppressed TNFα-induced IκB degradation, and in genetic knockout experiments, we found that the effect of salicylate on IκB degradation was AMPK-independent. Previous data also identified AMPK-independent regulation of glucose but we found that direct inhibition of neither NF-κB nor mTOR signalling suppressed glucose production, suggesting that other factors besides these cell signalling pathways may need to be considered to account for this response to salicylate. We found, for example, that H4IIE cells were exquisitely sensitive to uncoupling with modest doses of salicylate, which occurred on a similar time course to another anti-hyperglycaemic uncoupling agent 2,4-dinitrophenol, while there was no discernible effect at all of two salicylate analogues which are not anti-hyperglycaemic. This finding supports much earlier literature suggesting that salicylates exert anti-hyperglycaemic effects at least in part through uncoupling.

    Original languageEnglish
    Pages (from-to)1412-1422
    Number of pages11
    JournalBBA Molecular Basis of Disease
    Volume1862
    Issue number8
    Early online date27 Apr 2016
    DOIs
    Publication statusPublished - 1 Aug 2016

    Keywords

    • AMPK
    • Gluconeogenesis
    • MTOR signalling
    • NF-κB signalling
    • Salicylate

    ASJC Scopus subject areas

    • Molecular Biology
    • Molecular Medicine

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  • Cite this

    Cameron, A. R., Logie, L., Patel, K., Bacon, S., Forteath, C., Harthill, J., Roberts, A., Sutherland, C., Stewart, D., Viollet, B., Sakamoto, K., McDougall, G. J., Foretz, M., & Rena, G. (2016). Investigation of salicylate hepatic responses in comparison with chemical analogues of the drug. BBA Molecular Basis of Disease, 1862(8), 1412-1422. https://doi.org/10.1016/j.bbadis.2016.04.015