Altered hepatic catabolism of low-density lipoprotein subjected to lipid peroxidation in vitro

Abstract

Recent evidence suggests that oxidatively modified forms of low-density lipoprotein (LDL) may be particularly atherogenic. In this investigation, the catabolism of human LDL modified by lipid peroxidation in vitro was studied with a recirculating rat liver perfusion system. A dual-labelling technique was used that permitted native LDL and modified LDL to be studied simultaneously in the liver perfusion system. Native human LDL was found to have a fractional catabolic rate (FCR) of 1.00 +/- 0.21%/h, in agreement with other investigators. Subjecting LDL to oxidation for 12 h in the presence of 30 microM FeEDTA did not significantly affect its FCR. LDL treated with a superoxide-generating system (xanthine oxidase, hypoxanthine, O2) in the presence of 30 microM FeEDTA did, however, show a significant increase in FCR (3.23 +/- 0.19%/h). The hepatic uptakes of native LDL and LDL oxidized with FeEDTA+O2 were similar, but both were significantly lower than the hepatic uptake of LDL treated with the superoxide-radical-generating system. The proteolysis of LDL with pancreatin did not influence either its susceptibility to oxidation or its FCR. LDL oxidation resulted in the preferential loss of alpha-tocopherol rather than gamma-tocopherol. These data indicate that the rat liver effectively catabolizes LDL oxidatively modified by treatment with the superoxide-generating system. Furthermore, our results suggest that only very low plasma levels of highly oxidized LDL could be found under conditions in vivo. The liver may therefore play a major role in protecting the arterial vasculature from highly atherogenic forms of LDL.

Pulsatile Versus Oscillatory Shear Stress Regulates NADPH Oxidase Subunit Expression

“…12 Three possible sources proposed for LDL Ϫ are the following: (1) oxidation of LDL entrapped in the arterial wall, 13 (2) ingestion of oxidants or generation from postprandial lipoprotein remnants, 14 and (3) oxidation in plasma. 15 The NADH/NADPH oxidases are multimeric enzymes composed of plasma membrane-associated proteins as well as cytosolic factors. For the phagocytic-type NADPH oxidase, the plasma membrane-associated proteins gp91 phox and p22 phox comprise the flavocytochrome b558 complex, which forms the catalytic subunit of the oxidase.…”

Hypochlorite induces the formation of LDL−, a potentially atherogenic low density lipoprotein subspecies

“…Three possible sources of LDL 3 are discussed: (i) oxidation of LDL entrapped in the arterial wall [18], (ii) ingestion of oxidants or generation from postprandial lipoprotein remnants [19], and (iii) oxidation in plasma [20]. Our study reveals a potential role of HOCl in the generation of LDL 3 as a further mechanism.…”