Abstract
The aim of the present study was to analyze the direct effect of glucose in vitro on HDL-associated paraoxonase 1 (PON1) activity and stability, and on HDL-mediated macrophage cholesterol efflux. Furthermore, the above parameters were determined in HDL from diabetic patients in comparison to healthy subjects.
Incubation of serum from healthy subject (glucose levels lower than 100 mg%) with increasing concentrations of glucose (200–600 mg%) for 24 hours at 37 °C, resulted in a significant glucose dose-dependent reduction in paraoxonase activity in the serum and also in the HDL fraction (by up to 49). Enrichment of serum with glucose, up to 400 mg% significantly increased the inactivation rate of the free PON1 but not that of the HDL-bound PON1, by 7 fold.
Direct incubation of HDL with increasing glucose concentrations (0–400 mg%) for 24 hours at 37 °C resulted in a glucose dose-dependent decrement in HDL PON1 lactonase activity by up to 38%. In parallel, the HDLs ability to induce macrophage cholesterol efflux was reduced by up to 44%. Similarly, the lactonase activity of recombinant PON1 that was incubated with 400 mg% glucose was decreased by 31%, and this glucose-treated PON1 was not able to stimulate HDL-mediated macrophage cholesterol efflux, compared with the stimulatory effect of recombinant PON1 that was incubated without glucose. Furthermore, we were able to demonstrate by Western Blot analysis that glucose caused the dissociation of PON1 from the HDL, and this effect was glucose dose-dependent.
Finally, in diabetic patients, serum PON1 lactonase activity was significantly lower, by 60% vs. control healthy subjects. Analysis of serum PON1 stability, revealed that in diabetic patients the free PON1, as well as the HDL-bound PON1 inactivation rates were both significantly higher than those observed in the controls. Similarly, PON1 lactonase activity in HDL isolated from the diabetic patients vs. controls HDL was significantly lower by 77%. In addition, cholesterol efflux rate from J774 A.1 macrophages that was induced by diabetic patients HDL was significantly decreased by 53%, compared to the effect of HDL from healthy subjects. We thus conclude that PON1 inactivation and dissociation from HDL by high glucose concentrations may be responsible for the accelerated atherosclerosis in diabetic patients
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Rosenblat, M., Sapir, O., Aviram, M. (2008). Glucose Inactivates Paraoxonase 1 (PON1) and Displaces it from High Density Lipoprotein (HDL) to a Free PON1 Form. In: Mackness, B., Mackness, M., Aviram, M., Paragh, G. (eds) The Paraoxonases: Their Role in Disease Development and Xenobiotic Metabolism. Proteins And Cell Regulation, vol 6. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-6561-3_2
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