Petri T. Kovanen

Receptor-Mediated Uptake of Lipoprotein-Cholesterol and Its Utilization for Steroid Synthesis in the Adrenal Cortex

Publisher Summary This chapter discusses the receptor-mediated uptake of lipoprotein cholesterol and its utilization for steroid synthesis in the adrenal cortex. It discusses the four model system (1)mouse adrenal tumor cells in culture (Y-1 clone) ,(2) rats treated in vivo with 4-aminopyrazolopyrimidine (4-APP), (3) bovine adrenal cortex ,and (4) Human fetal adrenal membranes to demonstrate the presence and physiological significance of low-density lipoprotein. The studies in the four model systems allow the formulation of a hypothetical working model to explain some aspects of cholesterol metabolism in the adrenal cortex. In this model, the adrenal is considered to have a small pool of metabolically active free cholesterol that is rapidly turning over. In the steady state, the input and output of cholesterol from this metabolically active cholesterol pool must be balanced. The net output of cholesterol from this pool occurs when cholesterol is converted to steroid hormones that are secreted from the gland and when cholesterol is esterified to form cholesteryl ester droplets. The adrenal gland contains at least two pools of cholesterol in addition to the metabolically active pool. One of these is a fixed pool of free cholesterol in cell membranes. The second pool of cholesterol is contained in storage droplets, where the cholesterol is esterified with fatty acids. These cholesteryl esters exert a buffer function that tends to stabilize the free cholesterol content of the adrenal gland during transient fluctuations in steroid demand. In the model systems, the endogenous synthesis of cholesterol in the adrenal is important in several situations: (1) when insufficient plasma lipoproteins are available, a situation that is probably never encountered in normal physiology, (2) transiently, when there is a sudden stimulus to steroid secretion and sufficient time has not elapsed for the full induction of lipoprotein receptor activity, and (3) when the rate of steroid synthesis is so great that maximal lipoprotein receptor activity cannot supply sufficient cholesterol and supplementary cholesterol synthesis within the gland is required.

EVOLUTION OF THE LDL RECEPTOR CONCEPT–FROM CULTURED CELLS TO INTACT ANIMALS

The initial observations in cultured fibroblasts made six years ago allowed the formulation of a series of hypotheses concerning LDL metabolism in tissues of animals and man. The most important of these hypotheses was that a large fraction of LDL was removed from plasma by a specific receptor-mediated uptake mechanism whose function was to supply cholesterol to extrahepatic cells. This hypothesis is strongly supported by genetic observations in patients with familial hypercholesterolemia and by studies of the four model systems discussed above. These studies by no means solve all of the important questions about LDL metabolism. We still need to know which tissues take up the most LDL; we need to know how much LDL is cleared by the liver and whether this clearance involves the same LDL receptor that operates in extra-hepatic cells; we need to know the mechanism for the clearance of the one-half to two-thirds of LDL that leaves the plasma by receptor-independent pathways; and finally we need to know how an abnormal accumulation of LDL in the plasma leads to the deposition of cholesterol in scavenger cells and produces atherosclerosis.