Imaging of hepatic low density lipoprotein receptors by radionuclide scintiscanning in vivo.

Abstract

The low density lipoprotein (LDL) receptor mediates the cellular uptake of plasma lipoproteins that are derived from very low density lipoproteins (VLDL). Most of the functional LDL receptors in the body are located in the liver. Here, we describe a radionuclide scintiscanning technique that permits the measurement of LDL receptors in the livers of intact rabbits. '231-labeled VLDL were administered intravenously, and scintigraphic images of the liver and heart were obtained at intervals thereafter. In seven normal rabbits, radioactivity in the liver increased progressively between 1 and 20 min after injection, while radioactivity in the heart (reflecting that in plasma) decreased concomitantly. In Watanabeheritable hyperlipidemic rabbits, which lack LDL receptors on a genetic basis, there was little uptake of 1231-labeled VLDL into the liver and little decrease in cardiac radioactivity during this interval. These findings demonstrate that the LDL receptor is necessary for the hepatic uptake of VLDL-derived lipoproteins in the rabbit. Two conditions that diminish hepatic LDL receptor activity, cholesterol-feeding and prolonged fasting, also reduced the uptake of 123I-labeled VLDL in the liver as measured by scintiscanning. The In experimental animals (2-5) and in man (6-8), the total number of LDL receptors in the body has been estimated by measuring the rate of disappearance of 125I-labeled LDL from the circulation. In animals, the number of receptors in various tissues can be estimated by removal of organs after intravenous administration of radiolabeled lipoproteins and measurement of the radioactive lipoprotein that has been taken up by those organs. Such studies have revealed that the vast bulk of LDL receptors in animals are in the liver (4, 9, 10) and that these hepatic receptors are subject to regulation (2,5,(10)(11)(12)(13). In rabbits, LDL receptor activity is suppressed by high cholesterol diets (11), by diets composed of wheat starch and casein (12), and by prolonged fasting (13). Conversely, LDL receptor activity is stimulated by agents that lower the cholesterol content of liver, such as bile acidbinding resins and inhibitors of cholesterol synthesis (2, 8).A method for the noninvasive measurement of LDL receptor activity in liver would be desirable, initially for experimental studies in animals, and eventually for clinical studies in humans. The possibility of such measurement emerges from recent advances in scintiscanning and computer techniques and in the availability of low-energy isotopes (14). Theoretically, these methods should allow quantitative estimates in vivo of the receptor-mediated uptake of radiolabeled lipoproteins in the liver.To this end, we administered 123I-labeled VLDL intravenously to rabbits and measured the uptake of the lipoprotein in livers of these animals by radionuclide scintiscanning. We have chosen VLDL as a ligand because this lipoprotein is converted in the bloodstream to IDL, which enters the liver rapidly, due to its content of apoprotein E (15,16). In ...

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