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Modulation of hepatic and extrahepatic LDL receptors : Involvement in the progression of atherosclerosis
Author(s) -
Newton Roger S.
Publication year - 1985
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430060206
Subject(s) - ldl receptor , cholestyramine , receptor , cholesterol , medicine , chemistry , endocrinology , catabolism , bile acid , reductase , low density lipoprotein , reverse cholesterol transport , lipoprotein , biochemistry , biology , enzyme
Extensive investigation over the past 2 decades has led to a far better understanding of the role of lipoproteins in the etiology and progression of atherosclerosis. Paramount to this understanding has been the elucidation of how cells recognize these macromolecular complexes and metabolize the lipids and proteins they transport. Because of their elevation in plasma of many individuals with premature coronary heart disease, low‐density lipoproteins (LDL) have received particular attention. As primary transporters of cholesterol to cells in mammalian tissues, LDL particles are removed from blood via specific cell surface receptors that facilitate their uptake. Once internalized and exposed to lysosomal enzymes, LDL particles are degraded, “freeing” their cholesterol to regulate cellular cholesterol synthesis and modulate the number of LDL receptors on the cell membrane. This high‐affinity, high‐capacity process has been termed the LDL receptor pathway and is functional in most tissues of the body, especially in liver where over 50%percnt; of the total body LDL degradation occurs. Liver is the target organ of bile acid sequestrants (cholestyramine/colestipol) and HMG‐CoA reductase inhibitors (compactin/mevinolin), both of which induce increased expression of LDL receptors by affecting hepatic cholesterol availability. Unlike liver, the arterial wall under normal conditions is not very active at degrading LDL via the classical LDL receptor pathway. However, when hypercholesterolemia occurs, especially when there is an LDL‐receptor deficiency, the arterial wall removes 20‐‐fold more LDL than normal and with a greater fractional catabolic rate. Thus other endocytotic pathways exist by which LDL can enter cells of the arterial wall. These pathways are not as actuely regulated as the classical LDL receptor pathway, and, as a result, the arterial wall cells, particularly smooth muscle cells and resident macrophages, accumulate cholesteryl esters. In this brief review, the importance of these receptors to the etiology and progression of atherosclerosis is discussed in detail and sites of possible pharmacological intervention are identified.