The glycolytic pathway to coronary heart disease: a hypothesis.
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.
Leyva
F
F
Wynn Department of Metabolic Medicine, Imperial College School of Medicine, London, UK.
Wingrove
C S
CS
Godsland
I F
IF
Stevenson
J C
JC
D000818:Animals; D003327:Coronary Disease / Q000209:etiology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D015228:Hypertriglyceridemia / Q000378:metabolism; D008954:Models, Biological; D014527:Uric Acid / Q000097:blood / Q000378:metabolism
D014527:Uric Acid; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases