LKB1 and the regulation of malonyl-CoA and fatty acid oxidation in muscle
| Autor: | Jeffery R. Barrow, David M. Thomson, H-J. Kim, William W. Winder, B. M. Condon, Natasha Fillmore, Jacob D. Brown |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Male
medicine.medical_specialty Physiology Endocrinology Diabetes and Metabolism Mice Inbred Strains AMP-Activated Protein Kinases Protein Serine-Threonine Kinases 5'-AMP-Activated Protein Kinase Mice chemistry.chemical_compound AMP-Activated Protein Kinase Kinases AMP-activated protein kinase Multienzyme Complexes Physiology (medical) Internal medicine medicine Animals Hypoglycemic Agents Phosphorylation Muscle Skeletal Protein kinase A Beta oxidation Mice Knockout chemistry.chemical_classification biology Myocardium Body Weight Fatty Acids AMPK Heart Ribonucleotides Aminoimidazole Carboxamide Adenosine Monophosphate Electric Stimulation Recombinant Proteins Pyruvate carboxylase Malonyl Coenzyme A Endocrinology Malonyl-CoA Enzyme Biochemistry chemistry biology.protein Female Oxidation-Reduction Protein Kinases Acetyl-CoA Carboxylase Muscle Contraction |
| Zdroj: | American Journal of Physiology-Endocrinology and Metabolism. 293:E1572-E1579 |
| ISSN: | 1522-1555 0193-1849 |
| DOI: | 10.1152/ajpendo.00371.2007 |
| Popis: | 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-β-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. |
| Databáze: | OpenAIRE |
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