Increased catabolism of native and cyclohexanedione-modified low density lipoprotein in subjects with myeloproliferative diseases.

Abstract

We previously demonstrated reduced levels of low density lipoprotein (LDL) cholesterol in association with increased total fractional catabolic rates (FCR( of LDL apoprotein B (apo B) in individuals with myeloproliferative diseases (MPD). The removal of LDL from plasma and interstitial fluid is mediated via receptor and nonreceptor pathways. We attempted to quantitate LDL catabolism via each of these pathways in subjects with MPD and control subjects. The total FCR of LDL apo B was measured using radiolabeled native LDL. The FCR of radiolabeled cyclohexanedione-modified LDL (CHD-LDL) was used to assess the nonreceptor-mediated catabolism of LDL. Total FCR (mean +/- SD) was elevated in MPD vs controls (0.78 +/- 0.32 vs 0.45 +/- 0.11, p less than 0.01). CHD-LDL FCR was also increased in MPD vs controls (0.62 +/- 0.53 vs 0.23 +/- 0.04, p less than 0.01). Studies of the plasma decay of radiolabeled native and CHD-LDL preparations after their injection into cynomolgus monkeys indicated that CHD-LDL preparations from MPD and controls were removed at the same rates in those primates and that all CHD-LDL preparations were catabolized more slowly than the native LDL preparations. Studies in vitro indicated that CHD modification of LDL significantly reduced the rate of degradation of this lipoprotein by a specific high-affinity receptor pathway in normal human monocyte-derived macrophages and cultured human fibroblasts. We conclude that the catabolism of both native and CHD-LDL apo B is increased in subjects with MPD. If CHD-LDL is a valid tracer of nonreceptor-mediated removal of native LDL in individuals with MPD, our results indicate that the reduced LDL cholesterol concentrations demonstrated in these subjects are associated with increased nonreceptor-mediated catabolism of LDL apo B. At this time, both neoplastic cells and activated monocyte-macrophages appear to be likely sites of these abnormalities.