These studies report the effects of dietary cholesterol and triglyceride on rates of receptor-dependent and receptor-independent LDL transport in the liver of the hamster. In animals fed diets enriched with 0.1, 0.25, or 1% cholesterol for 1 mo, receptor-dependent LDL transport in the liver was suppressed by 43, 63, and 77%, respectively, and there were reciprocal changes in plasma LDL-cholesterol concentrations. In addition, dietary triglycerides modified the effect of dietary cholesterol on hepatic LDL transport and plasma LDL concentrations so that at each level of cholesterol intake, polyunsaturated triglycerides diminished and saturated triglycerides accentuated the effect of dietary cholesterol. When animals were raised from weaning on diets containing small amounts of cholesterol, the decline in receptor-dependent LDL transport was nearly abolished by the addition of polyunsaturated or monounsaturated triglycerides, but was markedly augmented by the addition of saturated lipids. When animals raised on diets containing cholesterol and saturated triglycerides were returned to the low cholesterol, low triglyceride control diet, hepatic receptor-dependent LDL transport and plasma LDLcholesterol concentrations returned essentially to normal within 2 wk. Neither receptor-independent LDL transport nor the receptor-dependent uptake of asialofetuin was significantly altered by dietary cholesterol or triglyceride suggesting that the effect of these lipids on hepatic LDL receptor activity was specific and not due to a generalized alteration in the physiochemical properties of hepatic membranes. These studies demonstrate the important role of saturated triglycerides in augmenting the effect of cholesterol in suppressing hepatic LDL receptor activity and elevating LDL-cholesterol levels.

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 ...

The plasma concentration of cholesterol carried in low density lipoproteins is principally determined by the level of LDL receptor activity (P) and the LDL-cholesterol production rate (Jt) found in animals or man. This study delineates which saturated fatty acids alter JU and Jt and so increase the plasma LDL-cholesterol level. J' and Jt were measured in vivo in hamsters fed a constant level of added dietary cholesterol (0.12%) and triacylglycerol (10%), where the triacylglycerol contained only a single saturated fatty acid varying in chain length from 6 to 18 carbon atoms. After feeding for 30 d, the 12:0, 14:0, 16:0, and 18:0 fatty acids, but not the 6:0, 8:0, and 10:0 compounds, became significantly enriched in the liver total lipid fraction of the respective groups fed these fatty acids. However, only the 12:0, 14:0, and 16:0 fatty acids, but not the 6:0, 8:0, 10:0, and 18:0 compounds, suppressed J, increased Jt, and essentially doubled plasma LDL-cholesterol concentrations. Neither the 16:0 nor 18:0 compound altered rates of cholesterol synthesis in the extrahepatic organs, and both lowered the hepatic total cholesterol pool. Thus, the different effects of the 16:0 and 18:0 fatty acids could not be attributed to a difference in cholesterol delivery to the liver. Since these changes in LDL kinetics took place without an apparent alteration in external sterol balance, the regulatory effects of the 12:0, 14:0, and 16:0 fatty acids presumably are mediated through some change in a putative intrahepatic regulatory pool of sterol in the liver. (J.

The liver plays a key role in the regulation of circulating levels of low density lipoproteins (LDL) because it is both the site for the production of and the major organ for the degradation of this class of lipoproteins. In this study, the effects of feeding polyunsaturated or saturated triacylglycerols on receptor-dependent and receptor-independent hepatic LDL uptake were measured in vivo in the hamster. In control animals, receptor-dependent LDL transport manifested an apparent Km value of 85 mg/di (plasma LDL-cholesterol concentration) and reached a maximum transport velocity of 131 #g of LDL-cholesterol/hr per g, whereas receptorindependent uptake increased as a linear function of plasma LDL levels. Thus, at normal plasma LDL-cholesterol concentrations, the hepatic clearance rate of LDL equaled 120 and 9 pl/hr per g by receptor-dependent and receptor-independent mechanisms, respectively. As the plasma LDL-cholesterol was increased, the receptor-dependent (but not the receptor-independent) component declined. When cholesterol (0.12%) alone or in combination with polyunsaturated triacylglycerols was fed for 30 days, receptor-dependent clearance was reduced to 36-42 p1/hr per g, whereas feeding of cholesterol plus saturated triacylglycerols essentially abolished receptor-dependent LDL uptake (5 p1A/hr per g). When compared to the appropriate kinetic curves, these rmdings indicated that receptor-mediated LDL transport was suppressed =30% by cholesterol feeding alone and this was unaffected by the addition of polyunsaturated triacylglycerols to the diet. In contrast, receptor-dependent uptake was suppressed --90% by the intake of saturated triacylglycerols. As compared to polyunsaturated triacylglycerols, the intake of saturated lipids was also associated with significantly higher plasma LDL-cholesterol concentrations and lower levels of cholesteryl esters in the liver.In the steady state, the circulating level of cholesterol carried in low density lipoproteins (LDL) is determined by the rate of production of this class of lipoproteins relative to the rate at which it is removed from the circulation. In the normal hamster, rat, and rabbit and in man, 60-80% of LDL degradation apparently is mediated by LDL receptors, whereas the remainder is accomplished by receptor-independent mechanisms (1-5). Although LDL uptake can be identified in many different organs, recent studies carried out in vivo have shown that the liver is responsible for the uptake of 65-80o of the LDL that is cleared from the plasma in species like the hamster, rat, rabbit, and dog. Furthermore, in these same species >90%o of the hepatic uptake of LDL is receptor-mediated (refs. 4, 6, and 7 and unpublished data). It is likely that the same is true in man (8). Thus, in species for which quantitative data are available, approximately 85-90% of all LDL-receptor activity demonstrable in the live animal is found in the liver. It follows from these observations that any dietary or pharmacological manipulation that alters plasma LDL levels proba...

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