Palmitate inhibits liver glycolysis. Involvement of fructose 2,6-bisphosphate in the glucose/fatty acid cycle

Hue, Louis; Maisin, Liliane; Rider, Mark H.

doi:10.1042/bj2510541

Cited by 71 publications

(69 citation statements)

References 26 publications

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“…Significant changes in ATP or ADP concentrations are not observed in the presence of fatty acid, although there are small rises in citrate levels, which may bring about an allosteric inhibition of phosphofructokinase [32]. The decline in fructose 2,6-bisphosphate concentration, induced by fatty acid oxidation [7] has been confirmed by our studies. This decline, which has been attributed to an inhibition of 6-phosphofructo-2-kinase [7] brought about by the increase in citrate levels, also may contribute to the lowering of flux through phosphofructokinase.…”

Section: Discussionsupporting

confidence: 74%

“…These relationships are also apparent when hexanoate rather than palmitate is added ( Table I). The presence of fatty acid has no effect on the steady-state levels of glucose 6-phosphate or fructose 6-phosphate (Table I) but, as reported by [7], depresses fructose 2,6-bisphosphate concentrations, which are restored when the rate of fatty acid oxidation declines (Table I). …”

Section: Resultssupporting

confidence: 58%

“…One possibility, advanced by Hue et al [7] is that the catalysis of glucose phosphorylation by glucokinase is inhibited by long-chain acyl CoA [12,13]. However, in attempting to repeat their work we observed that oxida- tion of short-chain fatty acid is equally effective in impairing glycolysis.…”

Section: Introductioncontrasting

confidence: 48%

“…This decrease in glucose utilization is explained in part by the depression of 6-phosphofructo-1 -kinase activity by citrate together with a feedback inhibition of hexokinase as a result of accumulation of glucose 6-phosphate [4-61. More recently, palmitate has been shown to inhibit glycolysis in liver by a mechanism also associated with glucose sparing [7]. The inhibitory effects of fatty acid oxidation on hepatic glycolysis and glucose utilization have been attributed to an associated decrease in the cellular concentration of fructose 2,6-bisphosphate [7], the potent allosteric activator of 6-phosphofructo-1-kinase [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…More recently, palmitate has been shown to inhibit glycolysis in liver by a mechanism also associated with glucose sparing [7]. The inhibitory effects of fatty acid oxidation on hepatic glycolysis and glucose utilization have been attributed to an associated decrease in the cellular concentration of fructose 2,6-bisphosphate [7], the potent allosteric activator of 6-phosphofructo-1-kinase [8,9]. However, the major enzyme responsible for glucose phosphorylation in liver is glucokinase (hexokinase D), which is insensitive to glucose 6-phosphate [IO] but can be inhibited by the interaction of fructose 6-phosphate with a specific regulatory protein [l 11.…”

Section: Introductionmentioning

confidence: 99%

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Effects of fatty acid oxidation on glucose utilization by isolated hepatocytes

et al. 1993

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We have studied the inhibitory action of long-and short-chain fatty acids on hepatic glucose utilization in hepatocytes isolated from fasted rats. The rates of hepatic glucose phosphorylation and glycolysis were determined from the tritiated products of [2-'H] and [6-3H]glucose metabolism, respectively. The difference between these was taken as an estimate of the 'cycling' between glucose and glucose-6-phosphate. In the presence of 40 mM glucose this cycling was estimated at 0.68 pmol/min/g wet wt. Glucose phosphorylation was unaffected during palmitate and hexanoate oxidation to ketone bodies but glycolysis was inhibited. The rate of glucose cycling was increased during this phase to 1.25 pmol/min/g. Following the complete metabolism of the fatty acids, glycolysis was reinstated and cycling rates returned to control levels. Hepatic glucose cycling appears to be an important component of the glucose/fatty acid cycle.

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Section: Discussionsupporting

confidence: 74%

Section: Resultssupporting

confidence: 58%

Section: Introductioncontrasting

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of fatty acid oxidation on glucose utilization by isolated hepatocytes

et al. 1993

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Insulin-regulated protein kinases during postnatal development of rat heart

et al. 1998

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The control of glucose uptake and glycogen metabolism by insulin in target organs is in part mediated through the regulation of protein-serine/threonine kinases. In this study, the expression and phosphotransferase activity levels of some of these kinases in rat heart ventricle were measured to investigate whether they might mediate the shift in the energy dependency of the developing heart from glycogen to fatty acids. Following tail-vein injection of overnight fasted adult rats with 2 U of insulin per kg body weight, protein kinase B (PKB), the 70-kDa ribosomal S6 kinase (S6K), and casein kinase 2 (CK2) were activated (30-600%), whereas the MAP/extracellular regulated kinases (ERK)1 and ERK2 were not stimulated under these conditions. When the expression levels of the insulin-activated kinases were probed with specific antibodies in ventricular extracts from 1-, 10-, 20-, 50-, and 365-day-old rats, phosphatidylinositol 3-kinase (PI3K), PKB, S6K, and CK2 were downregulated (40-60%) with age. By contrast, ventricular glycogen synthase kinase-3beta (GSK3beta) protein levels were maintained during postnatal development. Similar findings were obtained when the expression of these kinases was investigated in freshly isolated ventricular myocytes, where they were detected predominantly in the cytosolic fraction of the myocytes. Compared to other adult rat tissues such as brain and liver, the levels of PI3K, PKB, S6K, and GSK3beta were relatively low in the heart. Even though CK2 protein and activity levels were reduced by approximately 60% in 365 day as compared to 1-day-old rats, expression of CK2 in the adult heart was as high as detected in any of the other rat tissues. The high basal activities of CK2 in early neonatal heart may be associated with the proliferating state of myocytes.

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Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years

Randle

1998

Diabetes Metab. Rev.

763

531

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Competition for respiration between substrates in animal tissues has been known for at least 80 Years. The most important interaction, quantitatively is between glucose and fatty acids. The starting point in 1963 for the so called Glucose Fatty Acid Cycle was the realisation that the metabolic relationship between glucose and fatty acids is reciprocal and not dependent. Glucose provision promotes glucose oxidation and glucose and lipid storage, and inhibits fatty acid oxidation. Provision of free fatty acids promotes fatty acid oxidation and storage, inhibits glucose oxidation and may promote glucose storage if glycogen reserves are incomplete. This review is concerned predominantly with evidence in man in vivo. In the authors opinion the evidence for inhibitory effects of fatty acids on whole body glucose utilization ad oxidation (predominantly muscles) is decisive and enzyme mechanisms mediating these effects are well established. There is also much evidence that fatty acid oxidation inhibits glucose oxidation and stimulates glucose formation in liver and again enzyme mechanism are known. A permissive role for fatty acids in the insulin secretory response of islet β‐cells has now been firmly established and can be visualised as a mechanism to protect continuing provision of respiratory substrate. Longer term exposure of islet β‐cells to fatty acids impairs the insulin secretory response to glucose and mechanisms are known. There is compelling evidence that fatty acid oxidation may impair glucose oxidation in uncontrolled Type 1 and Type 2 diabetes, but no convincing evidence that fatty acids have a role in diminished glucose storage (glycogen deposition) in Type 2 diabetes. The inhibition of glucose storage which may follow prolonged elevation of plasma FFA in man and experimental animals is associated with glycogen repletion whereas the inhibition of glucose storage in Type 2 diabetes is associated with glycogen depletion. The precise role of fatty acids in disturbed carbohydrate metabolism in Type 2 diabetes is an area where future progress is confidently predicted. Copyright © 1998 John Wiley & Sons, Ltd.

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Palmitate inhibits liver glycolysis. Involvement of fructose 2,6-bisphosphate in the glucose/fatty acid cycle

Cited by 71 publications

References 26 publications

Effects of fatty acid oxidation on glucose utilization by isolated hepatocytes

Effects of fatty acid oxidation on glucose utilization by isolated hepatocytes

Insulin-regulated protein kinases during postnatal development of rat heart

Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years

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