The effect of ionizing radiation on plasmatic lipoproteins.
Thèse de doctorat de l'Université Paris VI, 16/12/98
Lipoprotein metabolism has been studied in rats, hamsters, pigs and baboons, in the days which follow the whole body exposure to g radiation (4 to 10 Gy) or g/neutron (ratio = 115) radiation (4 Gy). Lipoproteins were separated by ultracentrifugation in a density gradient (1.006 1.210 g/ml) and lipids in plasma and in lipoprotein fractions were determined by enzymatic methods.
Cholesterolemia was increased few days after irradiation. LDL and/or HDL accumulated in plasma according to the species. The extent of these increases was dependent on the dose received by the animals and on the nature of the radiation.
After irradiation plasma levels of apolipoproteins (apos) AI and AIV were decreased while those of apo B and apo E were increased. Apolipoprotein synthesis was measured in vivo, in the liver and in the small intestinal mucosa of fasted rats, by the incorporation of 3H leucine, 2 days after a 8 Gy g irradiation. The decrease of apo AI and apo AIV concentrations can be explained by a reduced synthesis in the intestine. Corresponding levels of mRNA were not modified, suggesting that decrease of apolipoprotein syntheses after irradiation occurred at a post-transcriptional level. In the liver, synthesis of apo AI, apo AIV and apo E and mRNA levels were unchanged although apo E mRNA level tended to decrease. Hepatic apo B synthesis was decreased without any change in mRNA level and the B48/B100 ratio was increased. This reduced apo B synthesis did not result from reduced lipid availability for lipoprotein assembly since fatty acid and cholesterol syntheses (measured by 1-14C acetate incorporation and/or by the HMGCoA reductase activity) and VLDL-trialyceride secretion were increased after irradiation.
In hamsters, the activity of IIMGCoA reductase was also increased while cholesterol elimination was markedly decreased (-85% for cholesterol 7 a-hydroxylase activity).
Increase in plasma levels of apo B and apo E would be the result of a decreased catabolism of lipoproteins containing apo B or apo E. Liver apo B/E receptor number was not changed in rats 2 and 4 days after irradiation while this number tended to decrease in irradiated hamster when compared to pair-fed controls.
In addition irradiation generates free radicals that can promote lipoprotein modifications and so decrease their interaction with apo B/E receptors. Indeed after irradiation, HDLI (rats) and LDL (hamsters, baboons) were more susceptible to in vitro peroxidation as shown by the reduction of lag time of conjugated diene formation.
An inflammatory state appeared after irradiation as indicated by the, apo SAA (serum amyloid A) increase in plasma of irradiated hamsters. Great similarities between irradiation and inflammation effects on lipoprotein metabolism were observed suggesting that inflammatory mediators released after irradiation play a major role in radio-induced lipid metabolic perturbations.