The Randle cycle revisited: a new head for an old hat - PubMed (original) (raw)

Review

The Randle cycle revisited: a new head for an old hat

Louis Hue et al. Am J Physiol Endocrinol Metab. 2009 Sep.

Abstract

In 1963, Lancet published a paper by Randle et al. that proposed a "glucose-fatty acid cycle" to describe fuel flux between and fuel selection by tissues. The original biochemical mechanism explained the inhibition of glucose oxidation by fatty acids. Since then, the principle has been confirmed by many investigators. At the same time, many new mechanisms controlling the utilization of glucose and fatty acids have been discovered. Here, we review the known short- and long-term mechanisms involved in the control of glucose and fatty acid utilization at the cytoplasmic and mitochondrial level in mammalian muscle and liver under normal and pathophysiological conditions. They include allosteric control, reversible phosphorylation, and the expression of key enzymes. However, the complexity is formidable. We suggest that not all chapters of the Randle cycle have been written.

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Figures

Fig. 1.

The “glucose-fatty acid cycle,” a homeostatic mechanism to control circulating concentrations of glucose and fatty acids (adapted from Ref. 142). The term “cycle” is used here to describe a reciprocal control between glucose and fatty acid metabolism. The effect of glucose is mediated by insulin. LCFA, long-chain fatty acid; TAG, triacylglycerol; Pyr, pyruvate.

Fig. 2.

Mechanism of inhibition of glucose utilization by fatty acid oxidation. The extent of inhibition is graded and most severe at the level of pyruvate dehydrogenase (PDH) and less severe at the level of 6-phosphofructo-1-kinase (PFK) and glucose uptake. PDH inhibition is caused by acetyl-CoA and NADH accumulation resulting from fatty acid oxidation, whereas PFK inhbition results from citrate accumulation in the cytosol. The mechanism of inhibition of glucose uptake is not clear. These effects reroute glucose toward glycogen synthesis and pyruvate to anaplerosis and/or gluconeogenesis. See text for further details. CYTO, cytosol; MITO, mitochondria; GLUT4, glucose transporter 4; HK, hexokinase; Glc-6-P, glucose 6-phosphate; Fru-6-P, fructose 6-phosphate; CPT I, carnitine palmitoyltransferase I; β-ox, β-oxidation.

Fig. 3.

Control of PDH activity by covalent modification. Phosphorylation inactivates the enzyme, and dephosphorylation activates the enzyme. The 3 sites are located in the α-subunit of E1 (pyruvate decarboxylase), 1 of the 3 components of the PDH complex. See text for further details. PDK, pyruvate dehydrogenase kinase; PDP, pyruvate dehydrogenase phosphatase; P, phosphate.

Fig. 4.

AMP-activated protein kinase (AMPK) stimulation of glucose and fatty acid utilization. Activation of AMPK leads to acetyl-CoA carboxylase (ACC) inactivation, possibly together with malonyl-CoA decarboxylase (MCD) activation, which decreases malonyl-CoA concentration and hence, favors fatty acid oxidation. AMPK also stimulates glucose uptake and glycolysis, and the inhibition of glucose uptake by fatty acid oxidation no longer prevails. TZDs, thiazolidinediones; AICA, 5-aminoimidazole-4-carboxamide.

Fig. 5.

Mechanism of inhibition of fatty acid oxidation by glucose. This mechanism is mediated by malonyl-CoA, the concentration of which depends on ACC activity and which inhibits the entry of long-chain fatty acyl (LCFAcyl-CoA) moieties into mitochondria. This effect reroutes fatty acids toward esterification. In extrahepatic tissues, the effect of glucose is stimulated by insulin. See text for further details. ACL, ATP-citrate lyase; FAS, fatty acid synthase.

Fig. 6.

Stimulation of mitochondrial respiration by fatty acids. β-Oxidation of fatty acids stimulates mitochondrial oxygen consumption (JO2) and increases the NADH/NAD ratio and the mitochondrial membrane potential (ΔΨ). Substrate oxidation provides the electron transfer chain with electrons, which are transferred to oxygen. The redox free energy (ΔE) span is used to synthesize ATP (not shown) by an energy transduction system involving the electrochemical gradient of protons (the proton motive force, Δp) created by proton pumps located in the respiratory chain complexes 1, 3, and 4 and driven by ΔE. Efficient coupling between ATP synthesis and oxygen consumption (ATP/O) depends on 2 forces, ΔE and ΔΨ. Proton leaks and inefficient coupling between electron and proton fluxes (redox slipping) decrease the system efficiency.

Fig. 7.

Proton leaks, reverse electron flow, and reactive oxygen species (ROS) production. High values of ΔΨ prevent electron flow, favor proton leaks, and lead to reverse electron flow and eventually enhanced production of ROS. This process is worsened by the concomitant oxidation of glucose and probably contributes to glucose toxicity. See text for further details.

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The Randle cycle revisited: a new head for an old hat - PubMed (original) (raw)