Regulation of low density lipoprotein receptors by plasma lipoproteins from patients with abetalipoproteinemia.

Abstract

Despite an absence of low density lipoproteins (LDLs) and-chylomicron remnants from plasma, the rates of cholesterol synthesis or the number of LDL receptors expressed on freshly isolated cells from patients with abetalipoproteinemia are not markedly increased. These observations suggest that other lipoprotein particles present in the plasma of patients with abetalipoproteinemia may regulate LDL receptor activity and the rates of cellular cholesterol synthesis in this disorder. In the present report we have studied the effects of lipoprotein fractions from the plasma of normal subjects, patients with abetalipoproteinemia, and a patient with dysbetalipoproteinemia on the binding, internalization, and degradation of "SI-labeled LDL ('25I-LDL) by cultured human fibroblasts. LDL from normal subjects or the high density lipoprotein fraction HDL2 from the plasma of patients with abetalipoproteinemia effectively down-regulated LDL receptor activity (>50% inhibition at 20 jug of protein per ml). HDL2 from the plasma of patients with abetalipoproteinemia also effectively reduced the binding, internalization, and degradation of '25I-LDL by cultured human fibroblasts. 125I-HDL2 from the plasma of patients with abetalipoproteinemia was bound, internalized, and degraded by cultured human fibroblasts; this process was competitively inhibited by unlabeled normal LDL or HDL2 from abetalipoproteinemic plasma and was 1/6th to 1/8th times as high when 12I-HDL2 was incubated with fibroblasts from a patient with receptor-negative homozygous familial hypercholesterolemia. We conclude that lipoproteins present in the HDL2 fraction of plasma from patients with abetalipoproteinemia (which are relatively rich in apoprotein E) are effective regulators of LDL receptor activity in normal human fibroblasts. These in vitro findings may explain why the in vivo rates of cholesterol synthesis and the number of LDL receptors expressed on freshly isolated cells from patients with abetalipoproteinemia are not markedly increased.The importance of specific high-affinity receptors that facilitate the cellular uptake of plasma lipoproteins in the regulation of cholesterol homeostasis has been well documented (1,2). Two distinct receptors have been identified on hepatic cell membranes (3, 4). One of these, the low density lipoprotein (LDL or BE) receptor specifically recognizes lipoprotein particles that contain either apoprotein B (LDL) or certain apoprotein Erich high density lipoprotein particles (such as the HDLC particles, which can be induced in dog plasma by diets rich in cholesterol) (5). This LDL or B,E receptor is expressed in many tissues, including the liver and adrenal cortex, and appears to be identical to the specific high-affinity LDL receptors originally identified on cultured human fibroblasts (6), which are defective in patients with familial hypercholesterolemia .(7). A second receptor (the apoprotein E receptor) that recognizes only lipoproteins containing apoprotein E (e.g., HDLc and chylomicron remnants) has been shown t...

Adrenocortical Response to Adrenocorticotropin in Heterozygous Familial Hypercholesterolemia*

“…The present report represents an extension of previous studies in which an impaired response to ACTH stimulation was documented in patients with abetalipoproteinemia (7,8) and homozygous FH (13). In the latter study, urinary excretion of cortisol during ACTH stimulation was 33% of the normal value in two patients with receptor-negative homozygous FH, but was 57% of normal in a third patient with receptor-defective homozygous FH.…”

The Role of the Microsomal Triglygeride Transfer Protein in Abetalipoproteinemia

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Osmotic Cell Swelling Stimulates Receptor-Mediated Low Density Lipoprotein Endocytosis and Degradation

“…Normal human skin fibroblasts were cultured in McCoy's 5A medium supplemented with 10% human serum and antibiotics (Illingworth, Alam, Sundberg, Hagemenas and Layman 1983). When the cells were confluent, the original medium was replaced with medium containing 10% human lipoprotein-deficient serum for 48 h to maximally induce LDL receptor activity.…”