Journal of Lipid Research, Vol 34, 1919-1929, Copyright © 1993 by Lipid Research, Inc.

ARTICLES

Aggregation as well as chemical modification of LDL during oxidation is responsible for poor processing in macrophages

HF Hoff, N Zyromski, D Armstrong and J O'Neil
Department of Cell Biology, Cleveland Clinic Foundation, OH 44195.

Aggregation is a characteristic of extensively oxidized (ox-) LDL. We wished to determine whether this structural change contributed even more to the documented poor degradation in macrophages of ox-LDL than the chemical changes. When protein degradation of the soluble and insoluble portions of extensively ox-LDL was compared to that of acetyl LDL in mouse peritoneal macrophages (MPM), we found that the percent of internalized LDL that was degraded was lowest for the insoluble portion (insol. ox-LDL), intermediate for the soluble portion (sol. ox-LDL), and highest for the acetyl LDL, regardless of whether the binding and uptake mechanisms had been excluded, e.g., by performing appropriate pulse-chase studies. As the same order of degradation was found after long-term degradation under cell-free conditions by a mixture of cathepsin B and D, it is likely that poor degradation of ox-LDL by lysosomal proteases is partially responsible for the deficient processing of ox-LDL in MPM. However, when MPM were incubated in a pulse-chase design with LDL that was induced to aggregate by vortexing without oxidizing (vx-LDL), degradation over an 18-h interval of accumulated vx-LDL was almost as low (25%) as that of insol. ox-LDL (18%), in contrast to sol. ox-LDL (60%). Yet, in a cell-free system cathepsin degradation of vx-LDL was as efficient as that of acetyl LDL and LDL. Also, the differences in degradation between sol. and insol. ox-LDL were smaller than in MPM. Thus, it appears that alternative mechanisms to poor proteolysis of substrate were responsible for poor intracellular processing of such aggregated lipoproteins. These results suggest that, although the poorer processing of insol. ox-LDL than sol. ox-LDL may be due, in part, to more deficient proteolytic degradation, particle aggregation per se may play at least as important a role in such deficiencies. This may occur by such mechanisms as altered intracellular trafficking leading to poorer fusion in macrophages of phagosomes containing aggregated lipoproteins with lysosomes.
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