Decreased affinity of low density lipoprotein (LDL) particles for LDL receptors in patients with cholesteryl ester transfer protein deficiency

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Abstract
We have reported that the disorder of lipoprotein metabolism in hyperalphalipoproteinae‐mic patients with a deficiency of cholesteryl ester transfer protein (CETP) is characterized by the poly‐disperse low density lipoprotein (LDL) particles and the accumulation of cholesteryl ester (CE) in high density lipoprotein (HDL) particles, forming cholesterol‐induced HDL (HDLc)‐like particles. In the present study we have investigated the interaction of these abnormal LDL with LDL receptors of normal human fibroblasts. Since the ultracentrifugally separated LDL fraction (1.019 < d < 1.063 gmL‐1) from the CETP‐deficient patients contained HDLc‐like particles, these particles were removed by anti‐apolipoprotein (apo) A‐I immunoaffinity column chromatography. The lipoproteins eluted in the unbound fraction of this column did not contain apo A‐I, so this fraction was considered to be authentic LDL. The authentic LDL of the patients were deficient in CE and rich in triglycerides and apo B. The authentic LDL itself showed polydispersity, ranging in size from 23 nm to 30 nm. The affinity of these abnormal LDL particles for LDL receptors was analysed by a competitive assay in which cold LDL from the patients or control compete with 125I‐labelled LDL for fibroblast LDL receptors. The concentration of LDL particles at which 50% of 125I‐labelled normal LDL was replaced was two to three times higher for the patients than for the normal control. Therefore, the affinity of patient LDL was thought to be reduced compared to that of control LDL. These results demonstrate that CETP may play an important role in making LDL particles homogeneous and rich in CE. This modulation of LDL by CETP may enhance the affinity of LDL for LDL receptors to deliver cholesterol to peripheral tissues.

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