Malonyl-CoA, fuel sensing, and insulin resistance
| العنوان: | Malonyl-CoA, fuel sensing, and insulin resistance |
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| المؤلفون: | Asish K. Saha, Lee A. Witters, Neil B. Ruderman, Demetrios G. Vavvas |
| المصدر: | American Journal of Physiology-Endocrinology and Metabolism. 276:E1-E18 |
| بيانات النشر: | American Physiological Society, 1999. |
| سنة النشر: | 1999 |
| مصطلحات موضوعية: | medicine.medical_specialty, Physiology, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Allosteric regulation, chemistry.chemical_compound, Insulin resistance, AMP-activated protein kinase, Physiology (medical), Internal medicine, medicine, Animals, Humans, Carnitine O-palmitoyltransferase, Carnitine, Muscle, Skeletal, biology, Insulin, Acetyl-CoA carboxylase, medicine.disease, Malonyl Coenzyme A, Malonyl-CoA, Endocrinology, chemistry, Biochemistry, biology.protein, lipids (amino acids, peptides, and proteins), Insulin Resistance, Energy Metabolism, Signal Transduction, medicine.drug |
| الوصف: | Malonyl-CoA is an allosteric inhibitor of carnitine palmitoyltransferase (CPT) I, the enzyme that controls the transfer of long-chain fatty acyl (LCFA)-CoAs into the mitochondria where they are oxidized. In rat skeletal muscle, the formation of malonyl-CoA is regulated acutely (in minutes) by changes in the activity of the β-isoform of acetyl-CoA carboxylase (ACCβ). This can occur by at least two mechanisms: one involving cytosolic citrate, an allosteric activator of ACCβand a precursor of its substrate cytosolic acetyl-CoA, and the other involving changes in ACCβphosphorylation. Increases in cytosolic citrate leading to an increase in the concentration of malonyl-CoA occur when muscle is presented with insulin and glucose, or when it is made inactive by denervation, in keeping with a diminished need for fatty acid oxidation in these situations. Conversely, during exercise, when the need of the muscle cell for fatty acid oxidation is increased, decreases in the ATP/AMP and/or creatine phosphate-to-creatine ratios activate an isoform of an AMP-activated protein kinase (AMPK), which phosphorylates ACCβand inhibits both its basal activity and activation by citrate. The central role of cytosolic citrate links this malonyl-CoA regulatory mechanism to the glucose-fatty acid cycle concept of Randle et al. (P. J. Randle, P. B. Garland. C. N. Hales, and E. A. Newsholme. Lancet 1: 785–789, 1963) and to a mechanism by which glucose might autoregulate its own use. A similar citrate-mediated malonyl-CoA regulatory mechanism appears to exist in other tissues, including the pancreatic β-cell, the heart, and probably the central nervous system. It is our hypothesis that by altering the cytosolic concentrations of LCFA-CoA and diacylglycerol, and secondarily the activity of one or more protein kinase C isoforms, changes in malonyl-CoA provide a link between fuel metabolism and signal transduction in these cells. It is also our hypothesis that dysregulation of the malonyl-CoA regulatory mechanism, if it leads to sustained increases in the concentrations of malonyl-CoA and cytosolic LCFA-CoA, could play a key role in the pathogenesis of insulin resistance in muscle. That it may contribute to abnormalities associated with the insulin resistance syndrome in other tissues and the development of obesity has also been suggested. Studies are clearly needed to test these hypotheses and to explore the notion that exercise and some pharmacological agents that increase insulin sensitivity act via effects on malonyl-CoA and/or cytosolic LCFA-CoA. |
| تدمد: | 1522-1555 0193-1849 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::20e3996ffca555e396e99e1a41ba0b19Test https://doi.org/10.1152/ajpendo.1999.276.1.e1Test |
| رقم الانضمام: | edsair.doi.dedup.....20e3996ffca555e396e99e1a41ba0b19 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15221555 01931849 |
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