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The glycolytic pathway to coronary heart disease: a hypothesis
F Leyva1, C S Wingrove, I F Godsland
1Wynn Department of Metabolic Medicine, Imperial College School of Medicine, London, UK.
Insights
Insulin resistance syndrome links metabolic disturbances like hyperuricemia to heart disease. A defect in glyceraldehyde-3-phosphate dehydrogenase (GA3PDH) may explain this connection by altering glycolysis and uric acid production.
Area of Science:
- Metabolic disorders and cardiovascular disease pathogenesis.
Background:
- Coronary heart disease (CHD) is associated with metabolic disturbances forming cardiovascular risk clusters.
- The insulin resistance syndrome, including hyperuricemia, is linked to CHD, but the role of hyperuricemia is not fully explained.
- Glycolytic disturbances are observed in insulin resistance and hyperuricemia, suggesting a link through glucose metabolism.
Purpose of the Study:
- To explore the mechanistic link between insulin resistance, hyperuricemia, and hypertriglyceridemia.
- To investigate the potential role of glycolytic enzyme defects in these metabolic disturbances.
Main Methods:
- The study proposes a theoretical model based on existing literature and biochemical pathways.
- It focuses on the role of insulin's control over glycolysis and uric acid production.
- Examines the impact of potential defects in glyceraldehyde-3-phosphate dehydrogenase (GA3PDH) activity.
Main Results:
- Insulin resistance affects glycolysis, impacting uric acid production via phosphoribosylpyrophosphate (PPRP) and ribose-5-phosphate (R-5-P).
- Diminished GA3PDH activity, regulated by insulin, can lead to the accumulation of glycolytic intermediates.
- This accumulation may explain the co-occurrence of insulin resistance, hyperuricemia, and hypertriglyceridemia.
Conclusions:
- Defects in GA3PDH and its insulin responsiveness may be central to the metabolic syndrome associated with cardiovascular risk.
- Disturbances in a single glycolytic enzyme could significantly influence multiple metabolic risk factors for CHD.
Abstract:
Coronary heart disease (CHD) is pathogenetically linked to numerous metabolic disturbances. These are inextricably interrelated, constituting identifiable clusters or syndromes of cardiovascular risk. Prominent among these is the insulin resistance syndrome, whose components, including hyperuricemia, have all been linked to CHD pathogenesis. Many mechanisms have been put forward to account for the emergence of this syndrome, but none offer a satisfactory explanation for the involvement of hyperuricemia. Possible explanations relate to the observation of glycolytic disturbances in insulin-resistant and hyperuricemic states. This might be expected from the fact that uric acid production is linked to glycolysis and that glycolysis is controlled by insulin. Phosphoribosylpyrophosphate (PPRP) is an important metabolite in this respect. Its availability depends on ribose-5-phosphate (R-5-P), the production of which is governed by glycolytic flux. Diversion of glycolytic intermediates toward R-5-P, PPRP, and uric acid will follow if there is diminished activity of glyceraldehyde-3-phosphate dehydrogenase (GA3PDH), which is regulated by insulin. Serum triglyceride concentrations may also increase, as might be expected from accumulation of glycerol-3-phosphate. Thus, intrinsic defects in GA3PDH and a loss of its responsiveness to insulin, by causing accumulation of glycolytic intermediates, may explain the association between insulin resistance, hyperuricemia, and hypertriglyceridemia. This scenario raises the possibility that disturbances of a single glycolytic enzyme may be pivotal in the modulation of metabolic risk factors for CHD.