The mitochondrial carnitine palmitoyltransferase system: its broadening role in fuel homoeostasis and new insights into its molecular features

Jd, McGarry

doi:10.1042/bst0230321

Cited by 95 publications

(66 citation statements)

References 8 publications

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“…In contrast, the corresponding decrease in fatty acid oxidation (0.74 to 0.44) was 41%. This could be explained if, as has been suggested by previous studies in the rat (28,29), malonylCoA in muscle is compartmentalized and its concentrations in the vicinity of CPT1 and in whole muscle do not totally reflect each other (28,29). Given this context, it is worth noting that the concentration of malonyl-CoA in human muscle is ~10% of that in the rat (30) (Table 4) and that both absolute and relative changes, due to such factors as insulin and glucose (present study) and exercise (30), appear to be smaller and may be difficult to detect.…”

Section: Pn Båvenholm and Associatesmentioning

confidence: 57%

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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Section: Pn Båvenholm and Associatesmentioning

confidence: 57%

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

et al. 2000

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“…2 In the presence of the sense primer (5Ј-ATGTAACCCT-GAATGCACGGTGGGGAGGACAT-3Ј) of the 300 bp 5Ј-UTR and the antisense primer (5Ј-TCACTGGGGATGCAGCCACCAGCTCCATT-3Ј) of the 42-bp 5Ј-UTR, PCR using human genomic DNA as a template produced a 14.5-kb DNA fragment spanning these two 5Ј-UTRs. The PCR reaction was performed using Expand TM Long Template PCR system (Roche Molecular Biochemicals).…”

Section: Methodsmentioning

confidence: 99%

“…Malonyl-CoA serves as the active donor of two carbon atoms in fatty acid synthesis and strongly inhibits fatty acid ␤-oxidation by acting as a potent inhibitor of carnitine palmitoyltransferase I (1,2). Carnitine palmitoyltransferase I resides on the surface of the mitochondrial membrane and generates palmitoylcarnitine from palmitoyl-CoA.…”

mentioning

confidence: 99%

Cloning of Human Acetyl-CoA Carboxylase β Promoter and Its Regulation by Muscle Regulatory Factors

Lee

Moon

et al. 2001

Journal of Biological Chemistry

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The 280-kDa ␤-isoform of acetyl-CoA carboxylase (ACC␤) is predominantly expressed in heart and skeletal muscle, whereas the 265-kDa ␣-isoform (ACC␣) is the major ACC in lipogenic tissues. The ACC␤ promoter showed myoblast-specific promoter activity and was strongly induced by MyoD in NIH3T3 cells. Serial deletions of the promoter revealed that MyoD acts on the E-boxes located at positions ؊498 to ؊403 and on the proximal region including the 5-untranslated region. Destruction of the E-boxes at positions ؊498 to ؊403 by site-directed mutagenesis resulted in a significant decrease of MyoD responsiveness. The "TGAAA" at ؊32 to ؊28 and the region around the transcription start site play important roles in basal transcription, probably as a TATA box and an Inr element, respectively. Mutations of another E-box at ؊14 to ؊9 and a "GCCTGTCA" sequence at ؉17 to ؉24 drastically decreased the MyoD responsiveness. The novel cis-element GCCTGTCA was preferentially bound by MyoD homodimer in EMSA and conferred MyoD responsiveness to a luciferase reporter, which was repressed by the overexpression of E12. This finding is unique since activation via E-boxes is mediated by heterodimers of MyoD and E-proteins. We screened a human skeletal muscle cDNA library to isolate clones expressing proteins that bind to the region around the GCCTGTCA (؉8 to ؉27) sequence, and isolated Myf4 and Myf6 cDNAs. Electrophoretic mobility shift assay showed that recombinant Myf4 and Myf6 bind to this novel cis-element. Moreover, transient expression of Myf6 induced significant activation on the ACC␤ promoter or an artificial promoter harboring this novel cis-element. These findings suggest that muscle regulatory factors, such as MyoD, Myf4, and Myf6, contribute to the muscle-specific expression of ACC␤ via E-boxes and the novel cis-element GCCTGTCA.

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“…Palmitoyl-carnitine passes through a carnitine-acylcarnitine translocase to the inner part of the inner mitochondrial membrane, where a second coenzyme exchange takes place, opposite to the former one: carnitine palmitoyltransferase II converts fatty acylcarnitines into fatty acyl-CoAs, that can now undergo 13-oxidation in the mitochondrial matrix. More details on the carnitine palmitoyltransferases may be found in [19,20]. Long-chain carnitine acyltransferases are also found in peroxisomes, and in endoplasmic reticulum, that also exchange carnitine for coenzyme A and vice versa [20].…”

Section: Palmitoylcarnitine In Mitochondrial Fatty Acid Importmentioning

confidence: 99%

Palmitoylcarnitine, a surface‐active metabolite

1996

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Palmitoylcarnitine is a well-known intermediate in mitochondrial fatty acid oxidation. Less known are its properties as a snrfactant, with a capacity to solubilize biological membranes similar to that of many synthetic detergents used in the biochemical laboratory. Some of the physico-chemical properties of palmitoylcarnitine may help to explain the need for coenzyme A-carnitine-coenzyme A acyl exchange during mitochondrial fatty acid import. The amphiphilic character of palmitoylcarnitine may also explain its proposed involvement in the pathogenesis of myocardial ischemia.

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The mitochondrial carnitine palmitoyltransferase system: its broadening role in fuel homoeostasis and new insights into its molecular features

Cited by 95 publications

References 8 publications

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

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

Cloning of Human Acetyl-CoA Carboxylase β Promoter and Its Regulation by Muscle Regulatory Factors

Palmitoylcarnitine, a surface‐active metabolite

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