Crucial role for LKB1 to AMPKalpha2 axis in the regulation of CD36-mediated long-chain fatty acid uptake into cardiomyocytes

Daphna D. J. Habets, Will A. Coumans, Mohammed El Hasnaoui, Elham Zarrinpashneh, Luc Bertrand, Benoit Viollet, Bente Kiens, Thomas Elbenhardt Jensen, Erik A. Richter, Arend Bonen, Jan F. C. Glatz, Joost J. F. P. Luiken

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    83 Citationer (Scopus)

    Abstract

    Enhanced contractile activity increases cardiac long-chain fatty acid (LCFA) uptake via translocation of CD36 to the sarcolemma, similarly to increase in glucose uptake via GLUT4 translocation. AMP-activated protein kinase (AMPK) is assumed to mediate contraction-induced LCFA utilization. However, which catalytic isoform (AMPKalpha1 versus AMPKalpha2) is involved, is unknown. Furthermore, no studies have been performed on the role of LKB1, a kinase with AMPKK activity, on the regulation of cardiac LCFA utilization. Using different mouse models (AMPKalpha2-kinase-dead, AMPKalpha2-knockout and LKB1-knockout mice), we tested whether LKB1 and/or AMPK are required for stimulation of LCFA and glucose utilization upon treatment of cardiomyocytes with compounds (oligomycin/AICAR/dipyridamole) which induce CD36 translocation similar to that seen upon contraction. In AMPKalpha2 kinase-dead cardiomyocytes, the stimulating effects of oligomycin and AICAR on palmitate and deoxyglucose uptake and palmitate oxidation were almost completely lost. Moreover, in AMPKalpha2- and LKB1-knockout cardiomyocytes, oligomycin-induced LCFA and deoxyglucose uptake were completely abolished. However, the stimulatory effect of dipyridamole on palmitate uptake and oxidation was preserved in AMPKalpha2-kinase-dead cardiomyocytes. In conclusion, in the heart there is a signaling axis consisting of LKB1 and AMPKalpha2 which activation results in enhanced LCFA utilization, similarly to enhanced glucose uptake. In addition, an unknown dipyridamole-activated pathway can stimulate cardiac LCFA utilization by activating signaling components downstream of AMPK.
    OriginalsprogEngelsk
    TidsskriftBBA General Subjects
    Vol/bind1791
    Udgave nummer3
    Sider (fra-til)212-219
    Antal sider8
    ISSN0304-4165
    DOI
    StatusUdgivet - 2009

    Bibliografisk note

    CURIS 2009 5200 034

    Citationsformater