Malonyl CoA as a Metabolic Switch and a Regulator of Insulin Sensitivity

Ruderman, Neil B.; Saha, Asish K.; Vavvas, Demetrios G.; Kurowski, T. G.; Laybutt, D. Ross; Schmitz‐Peiffer, Carsten; Biden, Trevor J.; Kraegen, Edward W.

doi:10.1007/978-1-4899-1928-1_24

Cited by 35 publications

(31 citation statements)

References 25 publications

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“…It has been hypothesized that accumulation of acyl-CoA in skeletal muscle causes insulin resistance (1)(2)(3)8) and that the concentration of acyl-CoA inversely correlates with insulin sensitivity (17,19). The effect of acyl-CoA on regulation of enzymes, however, depends on the free concentration, for which the concentration of ACBP is the most important determinant (10).…”

Section: Discussionmentioning

confidence: 99%

“…alonyl-CoA, an intermediate in the synthesis of fatty acids, inhibits carnitine palmitoyltransferase (CPT)-1 and therefore transport of acyl-CoA into the mitochondria for ␤-oxidation (1)(2)(3). The concentration of malonyl-CoA is increased in skeletal muscles from insulin-resistant rats (4 -6), and the resulting accumulation of acyl-CoA has been hypothesized to cause insulin resistance (1)(2)(3).…”

mentioning

confidence: 99%

“…The concentration of malonyl-CoA is increased in skeletal muscles from insulin-resistant rats (4 -6), and the resulting accumulation of acyl-CoA has been hypothesized to cause insulin resistance (1)(2)(3). AcylCoA is the metabolic active form of fatty acids used for ␤-oxidation and glycerolipid synthesis; however, acyl-CoA is also an important regulator of enzyme activities, ion channels, and gene expression (7)(8)(9)(10).…”

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Acyl-CoA Binding Protein Expression Is Fiber Type- Specific and Elevated in Muscles From the Obese Insulin-Resistant Zucker Rat

et al. 2002

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Accumulation of acyl-CoA is hypothesized to be involved in development of insulin resistance. Acyl-CoA binds to acyl-CoA binding protein (ACBP) with high affinity, and therefore knowledge about ACBP concentration is important for interpreting acyl-CoA data. In the present study, we used a sandwich enzyme-linked immunosorbent assay to quantify ACBP concentration in different muscle fiber types. Furthermore, ACBP concentration was compared in muscles from lean and obese Zucker rats. Expression of ACBP was highest in the slow-twitch oxidative soleus muscle and lowest in the fast-twitch glycolytic white gastrocnemius (0.46 ؎ 0.02 and 0.16 ؎ 0.005 g/mg protein, respectively). Expression of ACBP was soleus > red gastrocnemius > extensor digitorum longus > white gastrocnemius. Similar fiber type differences were found for carnitine palmitoyl transferase (CPT)-1, and a correlation was observed between ACBP and CPT-1. Muscles from obese Zucker rats had twice the triglyceride content, had approximately twice the long-chain acyl CoA content, and were severely insulin resistant. ACBP concentration was ϳ30% higher in all muscles from obese rats. Activities of CPT-1 and 3-hydroxy-acyl-CoA dehydrogenase were increased in muscles from obese rats, whereas citrate synthase activity was similar. In conclusion, ACBP expression is fiber type-specific with the highest concentration in oxidative muscles and the lowest in glycolytic muscles. The 90% increase in the concentration of acyl-CoA in obese Zucker muscle compared with only a 30% increase in the concentration of ACBP supports the hypothesis that an increased concentration of free acyl-CoA is involved in the development of insulin resistance. Diabetes 51:449 -454, 2002

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Section: Discussionmentioning

confidence: 99%

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Acyl-CoA Binding Protein Expression Is Fiber Type- Specific and Elevated in Muscles From the Obese Insulin-Resistant Zucker Rat

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“…Finally, sustained increases in the concentration of malonyl-CoA in muscle have been linked to insulin resistance in rodents (37), possibly by virtue of secondary increases in the cytosolic concentration of LCFA CoA and diacylglycerol-protein kinase C signaling. It has also been demonstrated that increases in plasma FFA are more likely to produce insulin resistance in this setting (29,38). In humans, insulin resistance can be produced experimentally by increasing plasma FFA levels (by infusing a lipid emulsion) during a euglycemichyperinsulinemic clamp (39)(40)(41)(42).…”

Section: A B Fatty Acid Oxidation and Malonyl-coa In Human Musclementioning

confidence: 99%

Fatty acid oxidation and the regulation of malonyl-CoA in human muscle.

et al. 2000

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Questions concerning whether malonyl-CoA is regulated in human muscle and whether malonyl-CoA modulates fatty acid oxidation are still unanswered. To address these questions, whole-body fatty acid oxidation and the concentration of malonyl-CoA, citrate, and malate were determined in the vastus lateralis muscle of 16 healthy nonobese Swedish men during a sequential euglycemichyperinsulinemic clamp. Insulin was infused at rates of 0.25 and 1.0 mU · kg -1 · min -1, and glucose was infused at rates of 2.0 ± 0.2 and 8.1 ± 0.7 mg · kg -1 · min -1 , respectively. During the low-dose insulin infusion, whole-body fatty acid oxidation, as determined by indirect calorimetry, decreased by 22% from a basal rate of 0.94 ± 0.06 to 0.74 ± 0.07 mg · kg -1 · min -1 (P = 0.005), but no increase in malonyl-CoA was observed. In contrast, during the highdose insulin infusion, malonyl-CoA increased from 0.20 ± 0.01 to 0.24 ± 0.01 nmol/g (P < 0.001), and whole-body fatty acid oxidation decreased by an additional 41% to 0.44 ± 0.06 mg · kg -1 · min -1 (P < 0.001). The increase in malonylCoA was associated with 30-50% increases in the concentrations of citrate (102 ± 6 vs. 137 ± 7 nmol/g, P < 0.001), an allosteric activator of the rate-limiting enzyme in the malonyl-CoA formation, acetyl-CoA carboxylase, and malate (80 ± 6 vs. 126 ± 9 nmol/g, P = 0.002), an antiporter for citrate efflux from the mitochondria. Significant correlations were observed between the concentration of malonyl-CoA and both glucose utilization (r = 0.53, P = 0.002) and the sum of the concentrations of citrate and malate (r = 0.52, P < 0.001), a proposed index of the cytosolic concentration of citrate. In addition, an inverse correlation between malonyl-CoA concentration and fatty acid oxidation was observed (r = -0.32, P = 0.03). The results indicate that an infusion of insulin and glucose at a high rate leads to increases in the concentration of malonyl-CoA in skeletal muscle and to decreases in whole-body and, presumably, muscle fatty acid oxidation. Furthermore, they suggest that the increase in malonyl-CoA in this situation is due, at least in part, to an increase in the cytosolic concentration of citrate. Because cytosolic citrate is also an inhibitor of phosphofructokinase, an attractive hypothesis is that changes in its concentration are part of an autoregulatory mechanism by which glucose modulates its own use and the use of fatty acids as fuels for skeletal muscle. Diabetes 49:1078-1083, 2000 M alonyl-CoA is an inhibitor of carnitine palmitoyl transferase-1 (CPT1), the enzyme that regulates the transfer of long-chain fatty acyl (LCFA) CoA into the mitochondria where they are oxidized (1). A recent study in humans indicated that during a euglycemic-hyperinsulinemic clamp, intracellular fatty acid oxidation is diminished in muscle due to inhibition of long-chain fatty acid entrance into the mitochondria (2); this finding is compatible with inhibition of CPT1 activity resulting from an increase in malonyl-CoA levels. Increases in malonyl-CoA concentrations oc...

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“…This is expected to predispose muscle cells to accumulate intracellular TAG when plasma NEFA are elevated, especially when blood glucose is also elevated. However, such intracellular TAG accumulation can be achieved without a prior increase in tissue malonyl-CoA if the supply of NEFA is high enough to exceed the maximal rate at which muscle can oxidize fatty acids [114]. Therefore elevated muscle malonyl-CoA levels are neither necessary nor sufficient to induce accumulation of TAG in insulin resistance, but are facilitative.…”

Section: Synthesis Of Glycerolipids In Muscle and Pancreatic β-Cellsmentioning

confidence: 99%

The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

Zammit

1999

Biochemical Journal

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Long-chain acyl-CoA esters have potent specific actions (e.g. on gene transcription, membrane trafficking) as well as non-specific ones (e.g. on phospholipid bilayers). They are synthesized on the cytosolic aspects of several intracellular membranes, to give rise to (a) cytosolic pool(s) to which a variety of enzymes and processes have access, including some localized in the nucleus. Their concentration in cells is highly regulated, interconversion with corresponding acylcarnitines being the most important mechanism involved. This reaction is catalysed by cytosol-accessible carnitine long-chain acyl (palmitoyl) transferase activities that are themselves located on multiple membrane systems. Regulation of these activities is through the inhibitory action of malonyl-CoA. Hence the existence of a potent malonyl-CoA-acyl-CoA axis through which many processes involved in the maintenance of mammalian cell function are regulated. The molecular, topographical and physiological interactions that make this possible are described and discussed.

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Malonyl CoA as a Metabolic Switch and a Regulator of Insulin Sensitivity

Cited by 35 publications

References 25 publications

Acyl-CoA Binding Protein Expression Is Fiber Type- Specific and Elevated in Muscles From the Obese Insulin-Resistant Zucker Rat

Acyl-CoA Binding Protein Expression Is Fiber Type- Specific and Elevated in Muscles From the Obese Insulin-Resistant Zucker Rat

Fatty acid oxidation and the regulation of malonyl-CoA in human muscle.

The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

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