LKB1 and the regulation of malonyl-CoA and fatty acid oxidation in muscle.
5'-AMP-activated protein kinase (AMPK), by way of its inhibition of acetyl-CoA carboxylase (ACC), plays an important role in regulating malonyl-CoA levels and the rate of fatty acid oxidation in skeletal and cardiac muscle. In these tissues, LKB1 is the major AMPK kinase and is therefore critical for AMPK activation. The purpose of this study was to determine how the lack of muscle LKB1 would affect malonyl-CoA levels and/or fatty-acid oxidation. Comparing wild-type (WT) and skeletal/cardiac muscle-specific LKB1 knockout (KO) mice, we found that the 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR)-stimulated decrease in malonyl-CoA levels in WT heart and quadriceps muscles was entirely dependent on the presence of LKB1, as was the AICAR-induced increase in fatty-acid oxidation in EDL muscles in vitro, since these responses were not observed in KO mice. Likewise, the decrease in malonyl-CoA levels after muscle contraction was attenuated in KO gastrocnemius muscles, suggesting that LKB1 plays an important role in promoting the inhibition of ACC, likely by activation of AMPK. However, since ACC phosphorylation still increased and malonyl-CoA levels decreased in KO muscles (albeit not to the levels observed in WT mice), whereas AMPK phosphorylation was entirely unresponsive, LKB1/AMPK signaling cannot be considered the sole mechanism for inhibiting ACC during and after muscle activity. Regardless, our results suggest that LKB1 is an important regulator of malonyl-CoA levels and fatty acid oxidation in skeletal muscle.
Thomson
D M
DM
Dept. of Physiology and Developmental Biology, Brigham Young Univ., Provo, UT 84602, USA.
Brown
J D
JD
Fillmore
N
N
Condon
B M
BM
Kim
H-J
HJ
Barrow
J R
JR
Winder
W W
WW
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000235:genetics; D004558:Electric Stimulation; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006321:Heart / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology
D005227:Fatty Acids; D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000249:Adenosine Monophosphate; D008316:Malonyl Coenzyme A; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase; C031143:AICA ribonucleotide