Copper deficiency-induced hypercholesterolemia: effects on HDL subfractions and hepatic lipoprotein receptor activity in the rat.

Male Sprague-Dawley rats (10 per group) were fed diets adequate (control) or deficient (CuDef) in copper for 6 wk. In the CuDef group, plasma total cholesterol, high density lipoprotein (HDL) cholesterol and apoA-I levels were significantly higher than in controls. Apolipoprotein analysis of the HDL fractions revealed a relative enrichment of apoE in the CuDef group. Size analysis of 1.21 density lipoproteins by nondenaturing gradient gel electrophoresis demonstrated the presence of more material migrating in the size range of HDL1 in the CuDef group. Separation of HDL into apoE-rich and apoA-I-rich fractions by heparin-affinity chromatography confirmed the presence of increased apoE-rich HDL in the CuDef group. To determine the mechanism responsible for higher apoE-rich HDL in the CuDef group, the lipoprotein receptor binding activity in hepatic membranes from the control and CuDef group was assayed. Kinetic analysis of the binding data revealed that the lipoprotein binding assay was primarily measuring the activity of the HDL receptor, which is not apoE mediated. When corrected for differential enrichment of plasma membrane, hepatic membranes from the CuDef group bound significantly fewer lipoproteins than did controls. Furthermore, the hepatic receptor binding activity was negatively correlated with the proportion of HDL enriched with apoE.