Resveratrol downregulates acetyl-CoA carboxylase alpha and fatty acid synthase by activating AMP-activated protein kinase and suppressing the mammalian target of rapamycin signal pathway

AMP-activated protein kinase (AMPK) has previously been demonstrated to phosphorylate and inactivate skeletal muscle acetyl-CoA carboxylase (ACC), the enzyme responsible for synthesis of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 and fatty acid oxidation. Contraction-induced activation of AMPK with subsequent phosphorylation/inactivation of ACC has been postulated to be responsible in part for the increase in fatty acid oxidation that occurs in muscle during exercise. These studies were designed to answer the question: Does phosphorylation of ACC by AMPK make palmitoyl-CoA a more effective inhibitor of ACC? Purified rat muscle ACC was subjected to phosphorylation by AMPK. Activity was determined on nonphosphorylated and phosphorylated ACC preparations at acetyl-CoA concentrations ranging from 2 to 500 μM and at palmitoyl-CoA concentrations ranging from 0 to 100 μM. Phosphorylation resulted in a significant decline in the substrate saturation curve at all palmitoyl-CoA concentrations. The inhibitor constant for palmitoyl-CoA inhibition of ACC was reduced from 1.7 ± 0.25 to 0.85 ± 0.13 μM as a consequence of phosphorylation. At 0.5 mM citrate, ACC activity was reduced to 13% of control values in response to the combination of phosphorylation and 10 μM palmitoyl-CoA. Skeletal muscle ACC is more potently inhibited by palmitoyl-CoA after having been phosphorylated by AMPK. This may contribute to low-muscle malonyl-CoA values and increasing fatty acid oxidation rates during long-term exercise when plasma fatty acid concentrations are elevated.

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Regulation of mammalian acetyl-CoA carboxylase

Biochemical Society Transactions ◽

10.1042/bst0301059 ◽

2002 ◽

Vol 30 (6) ◽

pp. 1059-1064 ◽

Cited By ~ 162

Author(s):

M. R. Munday

Keyword(s):

Fatty Acid ◽

Protein Kinase ◽

Critical Role ◽

Physiological Role ◽

Acid Synthesis ◽

Acid Oxidation ◽

Acetyl Coa Carboxylase ◽

Acetyl Coa ◽

Dependent Protein ◽

Amp Activated Protein Kinase

Acetyl-CoA carboxylase (ACC) plays a critical role in the regulation of fatty acid metabolism and its two isoforms, ACCα and ACCβ, appear to have distinct functions in the control of fatty acid synthesis and fatty acid oxidation, respectively. They are regulated by similar short-term mechanisms of allosteric activation by citrate, and reversible phosphorylation and inactivation, and there is clearly interaction between these mechanisms. AMP-activated protein kinase is the important physiological ACC kinase for both isoforms and yet there is a potential physiological role for cAMP-dependent protein kinase in the hormonally mediated inactivation of ACCα, and phosphorylation of ACCβ in its unique N-terminus.

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Lepin activates cardiac fatty acid oxidation independent of changes in the AMP-activated protein kinase-acetyl-CoA carboxylase-malonyl-CoA axis

Journal of Biological Chemistry ◽

10.1016/s0021-9258(20)68632-x ◽

2003 ◽

Vol 278 (24) ◽

pp. 22182

Author(s):

Laura L. Atkinson ◽

Melanie A. Fischer ◽

Gary D. Lopaschuk

Keyword(s):

Fatty Acid ◽

Protein Kinase ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Acetyl Coa Carboxylase ◽

Acetyl Coa ◽

Malonyl Coa ◽

Amp Activated Protein Kinase

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Influence of malonyl-CoA and palmitate concentration on rate of palmitate oxidation in rat muscle

Journal of Applied Physiology ◽

10.1152/jappl.1998.85.5.1909 ◽

1998 ◽

Vol 85 (5) ◽

pp. 1909-1914 ◽

Cited By ~ 32

Author(s):

G. F. Merrill ◽

E. J. Kurth ◽

B. B. Rasmussen ◽

W. W. Winder

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Protein Kinase ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Acetyl Coa Carboxylase ◽

Acetyl Coa ◽

Palmitate Oxidation ◽

Malonyl Coa ◽

Amp Activated Protein Kinase

5-Aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) is taken up by perfused skeletal muscle and phosphorylated to form 5-aminoimidazole-4-carboxamide-1-β-d-ribofuraosyl-5′-monophosphate (analog of 5′-AMP) with consequent activation of AMP-activated protein kinase, phosphorylation of acetyl-CoA carboxylase, decrease in malonyl-CoA, and increase in fatty acid oxidation. This study was designed to determine the effect of increasing levels of palmitate on the rate of fatty acid oxidation. Malonyl-CoA concentration was manipulated with AICAR at different palmitate concentrations. Rat hindlimbs were perfused with Krebs-Henseleit bicarbonate containing 4% bovine serum albumin, washed bovine red cells, 200 μU/ml insulin, 10 mM glucose, and different concentrations of palmitate (0.1–1.0 mM) without or with AICAR (2.0 mM). Perfusion with medium containing AICAR was found to activate AMP-activated protein kinase in skeletal muscle, inactivate acetyl-CoA carboxylase, and decrease malonyl-CoA at all concentrations of palmitate. The rate of palmitate oxidation increased as a function of palmitate concentration in both the presence and absence of AICAR but was always higher in the presence of AICAR. These results provide additional evidence that malonyl-CoA is an important regulator of the rate of fatty acid oxidation at palmitate concentrations in the physiological range.

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