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Malonyl-CoA decarboxylase - an overview | …

N2 - There seems to be an association between increased concentrations of malonyl coenzyme A (malonyl CoA) in skeletal muscle and diabetes and/or insulin resistance. The purpose of the current study was to test the hypothesis that treatments designed to manipulate malonyl CoA concentrations would affect insulin-stimulated glucose transport in cultured C2C12 myotubes. We assessed glucose transport after polyamine-mediated delivery of malonyl CoA to myotubes, after incubation with dichloroacetate (which reportedly increases malonyl CoA levels), or after exposure of myotubes to 2-bromopalmitate, a carnitine palmitoyl transferase I inhibitor. All three of these treatments prevented stimulation of glucose transport by insulin. We also assayed glucose transport after 30min of inhibition of acetyl coenzyme A carboxylase (ACC), the enzyme which catalyzes the production of malonyl CoA. Three unrelated ACC inhibitors (diclofop, clethodim, and Pfizer CP-640186) all enhanced insulin-stimulated glucose transport. However, none of the treatments designed to manipulate malonyl CoA concentrations altered markers of proximal insulin signaling through Akt. The findings support the hypothesis that acute changes in malonyl CoA concentrations affect insulin action in muscle cells but suggest that the effects do not involve alterations in proximal insulin signaling.

Malonyl-CoA can be formed within the mitochondria, peroxisomes, and cytosol of mammalian cells

A more serious problem than transient lowering of malonyl-CoA occurs in individuals who harbor genetic deficiencies in the enzymes that control carnitine levels and fat oxidation. Systemic carnitine deficiency due to a mutation in the carnitine transporter OCTN2 was the first identified cause of the syndrome of hypoketotic hypoglycemia, which can lead to sudden infant death (). Carnitine deficiency also causes liver failure, high ammonia, cerebral edema, cardiac arrhythmias, cardiomyopathy, and muscle weakness with rhabdomyolysis.

Malonyl-CoA decarboxylase deficiency ..

These findings explain the paradoxical fructoseeffect on food intake and lend credence to the malonyl-CoA hypothesis.

My colleague Denis McGarry and I knew early that fatty acid synthesis and oxidation were reciprocal, but it was unclear how this relationship was regulated. We initially thought control was on the lipogenic side, but when we acutely blocked fatty acid oxidation, there was an immediate resumption of fatty acid and triglyceride synthesis, indicating that an inhibitor of fatty acid oxidation must be regulating the process. We were faced with two challenges: identifying the inhibition point and identifying what controlled it. To investigate this, we next compared ketogenesis from octanoic and oleic acids. We knew octanoate could penetrate the mitochondrion freely, and we found that ketogenesis from it was identical in both fed and fasted states. Octanoate oxidation, therefore, is a measure of the capacity of the β-oxidative system. Oleate, in contrast, has to be transesterified from oleyl-CoA to oleylcarnitine by the enzyme carnitine palmitoyltransferase 1 (CPT1) to enter the mitochondria. The rate of oleate oxidation increased six-fold between the fed and fasted states. Thus, we concluded that regulation was occurring at the level of CPT1 ().

What was the inhibitor? We knew that there was a decrease in glycogen that accompanied the increase in ketogenesis. We tested dozens of molecules on CPT1, and none of them altered its activity. One morning McGarry came into the lab and said, “It has to be malonyl-CoA. It is the substrate for fatty acid synthesis, and it must also be the inhibitor.” Indeed, we were able to test this directly, and the data bore out his insightful hypothesis (, ).

The human MLYCD gene encoding malonyl-CoA decarboxylase ..

It is quite remarkable how many distinguished scientists began to study ketogenesis decades ago, among them the Nobel laureates Professors H.A. Krebs and Feodor Lynen. Early on, a widespread belief was that a deficiency of oxaloacetate in the tricarboxylic acid cycle shunted acetyl-CoA derived from fatty acid oxidation into acetoacetate, as described in an excellent lecture on this history published by Professor Krebs in 1966 (). Indeed, acetoacetate is the preferred metabolic substrate in mammalian cells, chosen above glucose, fatty acids, and other substrates (, ). However, oxidation of acetoacetate requires the enzyme succinyl-CoA:3-ketoacid-CoA transferase, which is not present in the liver; thus, the liver cannot oxidize ketones, only release them.

In the catabolic state with no food intake, the liver generates ketones by breaking down fatty acids. During the nocturnal fast or longer starvation periods, this protects the brain, which cannot oxidize fatty acids. In 1977, we published a study in the JCI noting the surprising realization that malonyl-CoA, the substrate of fatty acid synthesis, was also an inhibitor of fatty acid oxidation. Subsequent experiments have borne out this finding and furthered our understanding of molecular metabolism.

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supporting the hypothesis that hypothalamic malonyl-CoA, ..

There seems to be an association between increased concentrations of malonyl coenzyme A (malonyl CoA) in skeletal muscle and diabetes and/or insulin resistance. The purpose of the current study was to test the hypothesis that treatments designed to manipulate malonyl CoA concentrations would affect insulin-stimulated glucose transport in cultured C2C12 myotubes. We assessed glucose transport after polyamine-mediated delivery of malonyl CoA to myotubes, after incubation with dichloroacetate (which reportedly increases malonyl CoA levels), or after exposure of myotubes to 2-bromopalmitate, a carnitine palmitoyl transferase I inhibitor. All three of these treatments prevented stimulation of glucose transport by insulin. We also assayed glucose transport after 30min of inhibition of acetyl coenzyme A carboxylase (ACC), the enzyme which catalyzes the production of malonyl CoA. Three unrelated ACC inhibitors (diclofop, clethodim, and Pfizer CP-640186) all enhanced insulin-stimulated glucose transport. However, none of the treatments designed to manipulate malonyl CoA concentrations altered markers of proximal insulin signaling through Akt. The findings support the hypothesis that acute changes in malonyl CoA concentrations affect insulin action in muscle cells but suggest that the effects do not involve alterations in proximal insulin signaling.

Malonyl-CoA Synthetase, Encoded by ACYL …

T1 - Overexpression of a Modified Human Malonyl-CoA Decarboxylase Blocks the Glucose-induced Increase in Malonyl-CoA Level but Has No Impact on Insulin Secretion in INS-1-derived (832/13) β-Cells

Malonyl-CoA decarboxylase inhibition suppresses fatty …

N2 - The long-chain acyl-CoA (LC-CoA) model of glucose-stimulated insulin secretion (GSIS) holds that secretion is linked to a glucose-induced increase in malonyl-CoA level and accumulation of LC-CoA in the cytosol. We have previously tested the validity of this proposal by overexpressing goose malonyl-CoA decarboxylase (MCD) in INS-1 cells, but these studies have been criticized due to: 1) the small insulin secretion response (2-4-fold) of the INS-1 cells used; 2) unknown contribution of the ATP-sensitive K+ (KATP) channel-independent pathway of GSIS in INS-1 cells, which has been implicated as the site at which lipids regulate insulin granule exocytosis; and 3) deletion of the N-terminal mitochondrial targeting sequence, but not the C-terminal peroxisomal targeting sequence in the goose MCD construct, raising the possibility that a significant fraction of the overexpressed enzyme was localized to peroxisomes. To address these outstanding concerns, INS-1-derived 832/13 cells, which exhibit robust KATP channel-dependent and -independent pathways of GSIS, were treated with a new adenovirus encoding human MCD lacking both its mitochondrial and peroxisomal targeting sequences (AdCMV-MCDΔ5), resulting in large increases in cytosolic MCD activity. Treatment of 832/13 cells with AdCMV-MCDΔ5 completely blocked the glucose-induced rise in malonyl-CoA and attenuated the inhibitory effect of glucose on fatty acid oxidation. However, MCD overexpression had no effect on KATP channel-dependent or -independent GSIS in 832/13 cells. Furthermore, combined treatment of 832/13 cells with AdCMV-MCDΔ5 and triacsin C, an inhibitor of long chain acyl-CoA synthetase that reduces LC-CoA levels, did not impair GSIS. These findings extend our previous observations and are not consistent with the LC-CoA hypothesis as originally set forth.

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