Abnormal regulation of LDL receptor activity and abnormal cellular metabolism of hypertriglyceridaemic low density lipoprotein: normalization with bezafibrate therapy

Abstract

The regulation of LDL (B,E) receptor activity and of cellular LDL protein metabolism by hypertriglyceridaemic (HTG) low density lipoprotein before and during hypolipidaemic therapy (with bezafibrate (BZ)) were determined in cultured human skin fibroblasts. Defective binding and subnormal capacity to regulate LDL receptor activity was found for HTG-LDL. Binding affinity (Kd) of HTG-LDL to the receptor was 4.97 .times. 10-8 M and of N-LDL, 1.74 .times. 10-8 M. When assayed with normal 125I-LDL, the capacity of HTG-LDL to down-regulate receptor activity was 46-68% less than N-LDL. Both abnormalities reverted towards normal during treatment. The cellular metabolism of HTG-, BZ- and N-LDL in cells grown for 48 h with the respective lipoproteins was determined. In spite of their defective binding to the receptor, the metabolism of HTG-LDL in the regulated cells was accelerated in comparison to N-LDL, and equal to that of BZ-LDL. That observation is explained by the inefficient ability of HTG-LDL to depress LDL receptor activities in the cells.