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In silico evidence for gluconeogenesis from fatty acids in humans.

Kaleta C, de Figueiredo LF, Werner S, Guthke R, Ristow M, Schuster S - PLoS Comput. Biol. (2011)

Bottom Line: Analyzing the detected pathways in detail we found that their energetic requirements potentially limit their capacity.This study has many other biochemical implications: effect of starvation, sports physiology, practically carbohydrate-free diets of inuit, as well as survival of hibernating animals and embryos of egg-laying animals.Moreover, the energetic loss associated to the usage of gluconeogenesis from fatty acids can help explain the efficiency of carbohydrate reduced and ketogenic diets such as the Atkins diet.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioinformatics, School of Biology and Pharmaceutics, Friedrich Schiller University of Jena, Jena, Germany. christoph.kaleta@uni-jena.de

ABSTRACT
The question whether fatty acids can be converted into glucose in humans has a long standing tradition in biochemistry, and the expected answer is "No". Using recent advances in Systems Biology in the form of large-scale metabolic reconstructions, we reassessed this question by performing a global investigation of a genome-scale human metabolic network, which had been reconstructed on the basis of experimental results. By elementary flux pattern analysis, we found numerous pathways on which gluconeogenesis from fatty acids is feasible in humans. On these pathways, four moles of acetyl-CoA are converted into one mole of glucose and two moles of CO₂. Analyzing the detected pathways in detail we found that their energetic requirements potentially limit their capacity. This study has many other biochemical implications: effect of starvation, sports physiology, practically carbohydrate-free diets of inuit, as well as survival of hibernating animals and embryos of egg-laying animals. Moreover, the energetic loss associated to the usage of gluconeogenesis from fatty acids can help explain the efficiency of carbohydrate reduced and ketogenic diets such as the Atkins diet.

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Classical scheme of the interconversion between glucose and fatty acids in humans.A While the conversion of glucose into fatty acids is possible, the product of β-oxidation of even-chain fatty acids, acetyl-CoA, can only enter the TCA cycle by reaction with oxaloacetate to citrate. However, in order to replenish the oxaloacetate consumed in this reaction, the TCA cycle has to be used resulting in the release of two carbon atoms in form of carbon dioxide. Hence, while two carbon atoms enter the TCA cycle in form of acetyl-CoA two others are lost and a net production of oxaloacetate which would be required for gluconeogenesis is not possible. B In some organisms the carbon releasing steps of the TCA cycle can be bypassed using the glyoxylate shunt (thick dotted reactions). In consequence, one mole of oxaloacetate can be produced from two mole of acetyl-CoA, allowing for gluconeogenesis from fatty acids. A list of abbreviations can be found in Table S1.
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pcbi-1002116-g001: Classical scheme of the interconversion between glucose and fatty acids in humans.A While the conversion of glucose into fatty acids is possible, the product of β-oxidation of even-chain fatty acids, acetyl-CoA, can only enter the TCA cycle by reaction with oxaloacetate to citrate. However, in order to replenish the oxaloacetate consumed in this reaction, the TCA cycle has to be used resulting in the release of two carbon atoms in form of carbon dioxide. Hence, while two carbon atoms enter the TCA cycle in form of acetyl-CoA two others are lost and a net production of oxaloacetate which would be required for gluconeogenesis is not possible. B In some organisms the carbon releasing steps of the TCA cycle can be bypassed using the glyoxylate shunt (thick dotted reactions). In consequence, one mole of oxaloacetate can be produced from two mole of acetyl-CoA, allowing for gluconeogenesis from fatty acids. A list of abbreviations can be found in Table S1.

Mentions: It is well known that excess sugar in the human diet can be converted both into glycerol and fatty acids and, thus, into lipids such as triglycerides. A related question biochemistry students are often asked in their exams is whether the reverse route is also feasible, that is, whether the human body can convert fatty acids back into glucose. As for even-chain fatty acids, the expected answer is “No” (odd-chain fatty acids practically do not occur in mammals). This summarizes the result of a debate that dates back to the late 19th century. However, it was not until the 1950s that such a conversion could be monitored using 14C labeled fatty acids [1]. It was found that part of the label arrives at glucose, proving that there is a connected route from acetyl-CoA to glucose. However, as shown mathematically [1], [2], there cannot be any sustained conversion at steady state along the tricarboxylic acid (TCA) cycle due to stoichiometric constraints. In particular, oxaloacetate would not be balanced (Fig. 1A). A possible route that does allow this conversion in some prokaryotes [3], [4], plants [5], fungi [6] and nematodes [7] is the glyoxylate shunt. It produces an additional oxaloacetate, thus balancing this compound (Fig. 1B). However, the corresponding enzymes have not been found in mammals in spite of controversial speculations [8]. Reports that the glyoxylate shunt would be present in some hibernating animals [9] were not confirmed. In a recent experimental work they have been genetically introduced into mice [10].


In silico evidence for gluconeogenesis from fatty acids in humans.

Kaleta C, de Figueiredo LF, Werner S, Guthke R, Ristow M, Schuster S - PLoS Comput. Biol. (2011)

Classical scheme of the interconversion between glucose and fatty acids in humans.A While the conversion of glucose into fatty acids is possible, the product of β-oxidation of even-chain fatty acids, acetyl-CoA, can only enter the TCA cycle by reaction with oxaloacetate to citrate. However, in order to replenish the oxaloacetate consumed in this reaction, the TCA cycle has to be used resulting in the release of two carbon atoms in form of carbon dioxide. Hence, while two carbon atoms enter the TCA cycle in form of acetyl-CoA two others are lost and a net production of oxaloacetate which would be required for gluconeogenesis is not possible. B In some organisms the carbon releasing steps of the TCA cycle can be bypassed using the glyoxylate shunt (thick dotted reactions). In consequence, one mole of oxaloacetate can be produced from two mole of acetyl-CoA, allowing for gluconeogenesis from fatty acids. A list of abbreviations can be found in Table S1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140964&req=5

pcbi-1002116-g001: Classical scheme of the interconversion between glucose and fatty acids in humans.A While the conversion of glucose into fatty acids is possible, the product of β-oxidation of even-chain fatty acids, acetyl-CoA, can only enter the TCA cycle by reaction with oxaloacetate to citrate. However, in order to replenish the oxaloacetate consumed in this reaction, the TCA cycle has to be used resulting in the release of two carbon atoms in form of carbon dioxide. Hence, while two carbon atoms enter the TCA cycle in form of acetyl-CoA two others are lost and a net production of oxaloacetate which would be required for gluconeogenesis is not possible. B In some organisms the carbon releasing steps of the TCA cycle can be bypassed using the glyoxylate shunt (thick dotted reactions). In consequence, one mole of oxaloacetate can be produced from two mole of acetyl-CoA, allowing for gluconeogenesis from fatty acids. A list of abbreviations can be found in Table S1.
Mentions: It is well known that excess sugar in the human diet can be converted both into glycerol and fatty acids and, thus, into lipids such as triglycerides. A related question biochemistry students are often asked in their exams is whether the reverse route is also feasible, that is, whether the human body can convert fatty acids back into glucose. As for even-chain fatty acids, the expected answer is “No” (odd-chain fatty acids practically do not occur in mammals). This summarizes the result of a debate that dates back to the late 19th century. However, it was not until the 1950s that such a conversion could be monitored using 14C labeled fatty acids [1]. It was found that part of the label arrives at glucose, proving that there is a connected route from acetyl-CoA to glucose. However, as shown mathematically [1], [2], there cannot be any sustained conversion at steady state along the tricarboxylic acid (TCA) cycle due to stoichiometric constraints. In particular, oxaloacetate would not be balanced (Fig. 1A). A possible route that does allow this conversion in some prokaryotes [3], [4], plants [5], fungi [6] and nematodes [7] is the glyoxylate shunt. It produces an additional oxaloacetate, thus balancing this compound (Fig. 1B). However, the corresponding enzymes have not been found in mammals in spite of controversial speculations [8]. Reports that the glyoxylate shunt would be present in some hibernating animals [9] were not confirmed. In a recent experimental work they have been genetically introduced into mice [10].

Bottom Line: Analyzing the detected pathways in detail we found that their energetic requirements potentially limit their capacity.This study has many other biochemical implications: effect of starvation, sports physiology, practically carbohydrate-free diets of inuit, as well as survival of hibernating animals and embryos of egg-laying animals.Moreover, the energetic loss associated to the usage of gluconeogenesis from fatty acids can help explain the efficiency of carbohydrate reduced and ketogenic diets such as the Atkins diet.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioinformatics, School of Biology and Pharmaceutics, Friedrich Schiller University of Jena, Jena, Germany. christoph.kaleta@uni-jena.de

ABSTRACT
The question whether fatty acids can be converted into glucose in humans has a long standing tradition in biochemistry, and the expected answer is "No". Using recent advances in Systems Biology in the form of large-scale metabolic reconstructions, we reassessed this question by performing a global investigation of a genome-scale human metabolic network, which had been reconstructed on the basis of experimental results. By elementary flux pattern analysis, we found numerous pathways on which gluconeogenesis from fatty acids is feasible in humans. On these pathways, four moles of acetyl-CoA are converted into one mole of glucose and two moles of CO₂. Analyzing the detected pathways in detail we found that their energetic requirements potentially limit their capacity. This study has many other biochemical implications: effect of starvation, sports physiology, practically carbohydrate-free diets of inuit, as well as survival of hibernating animals and embryos of egg-laying animals. Moreover, the energetic loss associated to the usage of gluconeogenesis from fatty acids can help explain the efficiency of carbohydrate reduced and ketogenic diets such as the Atkins diet.

Show MeSH
Related in: MedlinePlus