期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
卷 1791, 期 3, 页码 212-219出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2008.12.009
关键词
AMPK; Cardiac substrate utilization; Cardiomyocyte; Contraction signalling; LKB1
资金
- Netherlands Organisation for Health Research and Development [912-04-075]
- European Community [LSHM-CT-2004-005272]
- Danish Medical Research Council
- Lundbeck Foundation
- Danish Ministry of Food, Agriculture and Fisheries
- Fonds National de la Recherche Scientifique et Medicale (Belgium)
- Actions de Recherches Concertees (Belgium)
- Heart and Stroke Foundation of Ontario
- Canada Research Chair in Metabolism and Health
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 (AMPK alpha 1 versus AMPK alpha 2) 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 (AMPK alpha 2-kinase-dead, AMPK alpha 2-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 AMPK alpha 2- kinase-dead cardiomyocytes, the stimulating effects of oligomycin and AICAR on palmitate and deoxyglucose uptake and palmitate oxidation were almost completely lost. Moreover, in AMPK alpha 2- 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 AMPK alpha 2-kinase-dead cardiomyocytes. In conclusion, in the heart there is a signaling axis consisting of LKB1 and AMPK alpha 2 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. (C) 2009 Elsevier B.V. All rights reserved.
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