Rates of receptor-dependent and -independent low density lipoprotein uptake in the hamster.

Abstract

By using a constant infusion technique in the hamster, rates of uptake of ['4C]sucrose-labeled hamster low density lipoprotein (hamLDL) and methylated hamster LDL (MehamLDL) were directly measured in 15 tissues. From these measurements the magnitude of LDL receptor-dependent-and receptor-independent lipoprotein transport was calculated. The whole-animal clearance of hamLDL equaled 547 p1I/hr per 100 g of body weight. LDL clearance per g of tissue was highest in the liver (114 pI/hr per g), ovary (43), spleen (36), adrenal gland (29), and intestine (24) and was lowest in fat (0.75), brain (0.35), and muscle (0.26). When adjusted for organ weight, the sum of the absolute clearance rates in all of the tissues examined equaled the rate of whole-animal LDL turnover. Liver accounted for 73%, and the jejunum and ileum combined accounted for 7% of wholeanimal clearance. The 12 other tissues each accounted for only a minor portion of LDL clearance. Rates of uptake of Me-hamLDL were much less in many tissues and accounted for only 6-12% of the uptake of LDL in the liver, ovary, adrenal gland,. lung, and kidney. However, this receptor-independent uptake was quantitatively more important in the intestine (44%) and spleen (72%) and accounted for essentially all LDL uptake in organs such as muscle, skin, and brain. Thus, in the hamster, most LDL is taken up and degraded by the liver. This uptake process is >90%o mediated by the LDL receptor and manifests saturation kinetics. Finally, cholestyramine feeding increases receptor-mediated LDL transport in the liver but in no other tissue studied.One critical determinant of the low density lipoprotein (LDL) concentration in plasma is the rate at which LDL is taken up and degraded by various organs. This uptake process involves at least two separate mechanisms, which have been termed receptor-dependent and receptor-independent transport. Receptor-dependent transport is a saturable process that involves binding of LDL molecules to specific receptors on the cell surface, followed by internalization and degradation (1, 2). Receptor-independent transport is poorly characterized but is probably a nonsaturable process (or processes) whereby LDL also is taken into cells and degraded. Receptor-independent clearance has generally been studied in isolated cells and in whole animals by measuring rates of uptake and degradation of LDL that has been modified chemically to block its interaction with the LDL receptor (3-5). Such studies indicate that in all species so far examined, the receptor-dependent and -independent mechanisms are both quantitatively important in determining rates of whole-animal LDL cholesterol turnover-(5-8).However, there is little information available on the actual rates of receptor-dependent and -independent LDL transport into specific organs under varying physiological circumstances. The data that are available have been derived largely by using techniques that only indirectly reflect the rates of transmembrane LDL movement, such as measurement of LDL binding ...

Increasing Hepatic Cholesterol 7α–Hydroxylase Reduces Plasma Cholesterol Concentrations in Normocholesterolemic and Hypercholesterolemic Rabbits

“…Food consumption was not reduced, and body rabbits, although receptor mRNA levels were similar in both weight was not decreased during bile fistula and glycodeoxyrabbit groups. However, as previously noted by Spady et al 35 cholic acid infusion periods. Bile flow was 3.4 { 0.6 and 3.6 and Stalenhoef et al, 36 in WHHL rabbits, the clearance of { 0.4 mL/h, respectively, in NZW and WHHL rabbits after cholesterol bound to LDL via the receptor-mediated pathway 5 days of bile drainage and increased 2.5 times (8.8 { 1.1 and was almost nil.…”

“…Because it is well known that LDL receptors are deficient a high intake of dietary cholesterol like a rat so that cholesterol 7a-hydroxylase was increased and the absorbed cholesor do not function properly in WHHL rabbits, 7,[35][36][37] it was of interest to note the considerable amounts of LDL receptor terol was converted efficiently to bile acids. Similar results have been reported for a selected group of rabbits who show mRNA and receptor-mediated binding that could be detected in the liver of these rabbits.…”

Regulation of plasma levels of low-density lipoprotein cholesterol: interpretation of data on low-density lipoprotein turnover in man.

“…4 The receptor-independent component of this uptake process can also be assessed with use of methylated heterologous LDL, which is not recognized by the LDL receptor.4 '5 When the appropriate regression curves are fitted to such data for determination of either total LDL uptake DIAGNOSTIC METHODS-LDL CHOLESTEROL (equation 3) or receptor-independent LDL transport (equation 2), the best-fit kinetic curves are obtained for each organ. Examples of such curves are shown in figure 1 for four organs of the hamster.…”

Fatty acids and CHD

“…Saturated fatty acids. SFA increase plasma total cholesterol and LDL-cholesterol levels by decreasing LDL receptor-mediated catabolism (Spady et al 1983;Nicolosi et al 1990). However, not all SFA affect total cholesterol and LDL-cholesterol concentrations in the same manner.…”