Crucial role for LKB1 to AMPKalpha2 axis in the regulation of CD36-mediated long-chain fatty acid uptake into cardiomyocytes.
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.
Habets
Daphna D J
DD
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, 6200 MD Maastricht, The Netherlands. d.habets@gen.unimaas.nl
Coumans
Will A
WA
El Hasnaoui
Mohammed
M
Zarrinpashneh
Elham
E
Bertrand
Luc
L
Viollet
Benoit
B
Kiens
Bente
B
Jensen
Thomas E
TE
Richter
Erik A
EA
Bonen
Arend
A
Glatz
Jan F C
JF
Luiken
Joost J F P
JJ
D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D018955:CD36 Antigens / Q000378:metabolism*; D003847:Deoxyglucose / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D019426:Integrases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D021381:Protein Transport; D012265:Ribonucleotides / Q000494:pharmacology; D012508:Sarcolemma / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology
D018955:CD36 Antigens; D005230:Fatty Acids, Nonesterified; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D009840:Oligomycins; D010168:Palmitates; D010975:Platelet Aggregation Inhibitors; D012265:Ribonucleotides; C495693:Slc2a4 protein, mouse; D014475:Uncoupling Agents; D000620:Aminoimidazole Carboxamide; D004176:Dipyridamole; D003847:Deoxyglucose; C534978:Prkaa2 protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C045073:Cre recombinase; D019426:Integrases; C031143:AICA ribonucleotide