A B S T R A C T This study examines the effects of increased dietary cholesterol (6 eggs/d) on the metabolism of low density lipoproteins in a group of seven healthy volunteers. Egg supplementation raised high density and low density lipoprotein cholesterol levels by 18 and 40%, respectively. The composition of the low density lipoprotein was unaltered and therefore the number of circulating particles must have increased. Kinetic studies indicated that this was due primarily to a 23% rise in the rate of synthesis of the lipoprotein. Catabolism was also affected. The fractional removal rate of native low density lipoprotein fell by 10% (P < 0.05). However, the clearance of the 1,2 cyclohexanedione-treated lipoprotein remained unchanged (control fractional clearance rate [FCR] = 0.188 pools/d; cholesterol feeding FCR = 0.183 pools/d). Therefore, the reduction in low density lipoprotein catabolism appeared to be due to a fall in receptor activity. Consequently, an increased sterol load (34.2 gmol/kg per d vs. 27.7 umol/kg per d in the control phase, P < 0.02) was channelled into the receptor-independent route during egg feeding.

Receptor-mediated catabolism of low density lipoprotein (LDL) by cultured cells depends on the presence of functionally significant arginine and lysine residues on the lipoprotein apoprotein. When these are blocked, the recognition process is abolished, and catabolism of the modified lipoprotein is restricted to other mechanisms. Accurate discrimination between the activities of the receptor and nonreceptor pathways in vivo depends critically on the metabolic properties of this chemically modified lipoprotein. Here we report our experiences with two lysine-modified LDL tracers, glucosylated LDL (GLC-LDL) and 2-hydroxyacetaldehyde-treated LDL (HOET-LDL). The fractional clearance rate of GLC-LDL (0.25 ± 0.05 pools/day, n = 5) was 50% of that of control material (0.51 ± 0.09 pools/day) injected simultaneously into normal subjects. The HOET-LDL was also retarded in its clearance. Here, however, the fractional clearances of the control (0.37 ± 0.06 pools/day, n = 6) and modified lipoprotein (0.19 ± 0.03 pools/day) were lower than those obtained by the glucosylation procedure. We suspect that the prolonged incubation required for glucosylation of LDL artifactually accelerated its catabolism. The HOET-LDL does not suffer from this defect and seems to be a better tracer of the receptor-independent pathway. In a group of 10 subjects, HOET-LDL was metabolically indistinguishable from 1,2 cyclohexanedione-treated, arginine-modified LDL. (Arteriosclerosis 4:604-613, November/December 1984) L ow density lipoprotein (LDL) catabolism occurs by at least two distinct pathways. 1 One of these is an autoregulated system responsible for the controlled delivery of LDL cholesterol to cells.2 The key component of this pathway is a high affinity receptor located on the cell surface membrane. It binds LDL and promotes its rapid transfer into the cell in endocytic vesicles. The lipoprotein is transported to lysosomes for degradation, while the receptor recycles to the cell surface to initiate further internalization. 3 The specificity of the receptor-lipoprotein interaction on the cell membrane is dependent on an electrostatic attraction between positively charged residues of arFrom the University Departments of Medical Cardiology and Biochemistry, Royal Infirmary, Glasgow, United Kingdom.This work was supported by Grant 81/6 from the British Heart Foundation and Grant G 8111558 SA from the Medical Research Council.Address for reprints: Dr. James Shepherd, Department of Biochemistry, Royal Infirmary, Glasgow G4 OSF, United Kingdom.Received November 10, 1983; revision accepted June 21, 1984. ginine 4 or lysine 5 on the lipoprotein apoprotein and complementary negative domains (as yet undefined) on the receptor. It is possible to abolish this interaction by selective modification of LDL at the critical arginine or lysine residues. Catabolism of the modified lipoprotein in vivo is therefore presumably restricted to pathways that do not involve the high affinity receptor and whose nature and locations are not yet identified.In earlier studie...

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