Intravenous apoA-I/lecithin discs increase pre-beta-HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans.

The extent to which plasma HDL concentration regulates reverse cholesterol transport (RCT) is not known. The principal acceptors of unesterified cholesterol (UC) from cultured cells are small pre-beta-HDL, which we have shown increase in plasma during intravenous infusion of apolipoprotein A-I/phosphatidylcholine (apoA-I/PC) discs in humans. We have now examined the effects on tissue fluid HDL and RCT. ApoA-I/PC or proapoA-I/PC discs were infused into 16 healthy males. Eleven had been given intravenous radiocholesterol to label tissue pools; in 12 prenodal leg lymph was collected throughout; and in 8 all feces were collected. The rise in small pre-beta-HDL in plasma was associated with increases in 1) pre-beta-HDL concentration in lymph (all subjects), 2) the size of other lymph HDL (four of four subjects), 3) the cholesterol content of lymph lipoproteins relative to plasma lipoproteins (P < 0.01, n = 4), 4) cholesterol-specific radioactivity in lymph (five of nine subjects), 5) plasma lathosterol (P < 0.004, n = 4), 6) plasma cholesterol esterification rate (P < 0.001, n = 4), and 7) fecal bile acid excretion (P < 0.001, n = 8). These results support the hypothesis that small pre-beta-HDL generated in plasma readily cross endothelium into tissue fluid, and thereby promote efflux of UC from peripheral cells. After delivery to the liver, peripheral cholesterol appears to be utilized more for bile acid synthesis than for biliary cholesterol secretion in humans.

Activation of the phagocytic system increases intimal proliferation in hypercholesterolemic rabbits.

The effect of in vivo stimulation of the phagocytic system (neutrophils, monocytes and hepatic Kupffer-cells) by inducing phagocytosis of intravenously administered latex particles on lipid peroxidation and aortic intimal proliferation was tested in cholesterol-fed rabbits. Three weeks after starting the diet, aortic intimal proliferation was measured by the intimal to medial ratios and by the incorporation of [3H]thymidine, infused into the circulation for the preceding 14 days. Intimal to medial ratios were increased (0.473 +/- 0.023 vs. 0.282 +/- 0.011, P < 0.01) and aortic [3H]thymidine contents were higher (66.8 +/- 3.5 vs. 27.8 +/- 49 counts/min per mg, P = 0.0001) in latex bead-treated than in control animals. Injection of beads transiently increased plasma lipid peroxide levels. At the end of the 3 week experiment, plasma lipid peroxide levels were still elevated and lipid peroxide contents of the aortic walls were higher in the latex-treated rabbits (82.8 +/- 5.8 vs. 46.4 +/- 4.9 nmol/mg cholesterol, latex-treated vs. controls, P = 0.004). These data suggest a significant acceleration of atherogenesis by the stimulated phagocytic system, the mechanism of which may involve lipid peroxidation.