ABSTRACT

The plasma clearance of radiolabeled chylomicrons was compared in normal, cholesterol-fed, and Watanabe heritable hyperlipidemic (WHHL) rabbits. Chylomicron clearance was rapid in normal rabbits but was significantly retarded in cholesterol-fed and WHHL rabbits. At 40 min after the injection of chylomicrons, 14-17% of the injected dose remained in the plasma of normal rabbits, whereas 40-50% of the injected dose remained in the plasma of cholesterol-fed and WHHL rabbits. The differences were reflected in the reduced plasma clearance by the liver and bone marrow of the cholesterol-fed and WHHL rabbits. The hyperlipidemic rabbits expressed normal levels of low density lipoprotein (LDL) receptor-related protein/-macroglobulin receptor in the liver. In contrast, the hepatic levels of LDL receptors were lower in hyperlipidemic rabbits; as expected, they were significantly lower in WHHL rabbits compared with normal and cholesterol-fed rabbits. Furthermore, it was demonstrated that lipoproteins accumulating in the plasma of the hyperlipidemic rabbits competed for and retarded the clearance of chylomicrons from the plasma. Competition was demonstrated by cross-circulation of normal and cholesterol-fed or normal and WHHL rabbits, in which the rapid influx of plasma containing the accumulated plasma lipoproteins from cholesterol-fed or WHHL rabbits was shown to impair the uptake of chylomicrons by the liver and bone marrow of normal rabbits. These observations were extended by infusing isolated lipoproteins into normal rabbits. The rabbit d < 1.02 g/ml (remnant) fraction and the canine cholesterol-rich high density lipoproteins (HDL) with apolipoprotein E (HDL) inhibited chylomicron clearance, whereas human LDL and HDL from humans and rabbits did not. We conclude that the low LDL receptor activity in the cholesterol-fed and WHHL rabbits may contribute, at least in part, to the impaired clearance by decreasing remnant uptake and causing the accumulation of chylomicron and/or very low density lipoprotein remnants. The accumulated remnant lipoproteins then compete for and saturate the mechanism responsible for the initial rapid clearance of chylomicrons from the plasma. We speculate that saturation of the initial rapid clearance may occur at the sequestration step, which involves the binding of remnants to heparan sulfate proteoglycans in the space of Disse.

INTRODUCTION

Chylomicrons are the major lipoproteins responsible for the transport of dietary lipids to various tissues. Lipoprotein lipase hydrolyzes triglycerides present in the core of chylomicrons, converting them to remnants. Chylomicron remnants are rapidly cleared from the plasma, and this process is mediated primarily by apolipoprotein E (apoE)() (for review, see Refs. 1-5).

It has been postulated that several steps are involved in chylomicron remnant clearance from the plasma and ultimate uptake of these lipoproteins by hepatocytes (1, 3, 5) . The initial process responsible for the normal rapid clearance of remnants from the plasma is thought to involve a sequestration of the particles in the space of Disse. This process may involve the binding of apoE on the remnants to heparan sulfate proteoglycans (HSPG) and the interaction of remnants with hepatic lipase (6, 7) . Several lines of evidence have now established that remnant lipoproteins bind initially to cell-surface HSPG and that, in the absence of HSPG, remnant binding and uptake are decreased even in the presence of a functional low density lipoprotein (LDL) receptor-related protein (LRP) (8, 9) . Presumably, remnant binding to HSPG is necessary for the LRP to mediate uptake. Further lipolytic processing in the space of Disse may occur before recognition of the lipoprotein particles by the lipoprotein receptors. It has been shown that lipoprotein lipase facilitates the binding of remnants to the LRP (10) and that hepatic lipase can stimulate the binding of remnants to HSPG and facilitate uptake of these particles presumably through the LRP (11) . Finally, uptake of the remnants via an apoE-mediated process appears to involve both the LDL receptor and the LRP (1, 2, 3, 4, 5) .

The LDL receptor has been shown in a variety of in vitro systems to mediate the uptake of apoE-containing remnant lipoproteins. Choi et al. (12) have inhibited uptake of chylomicrons using antibodies that block lipoprotein uptake by LDL receptors. Recently, several lines of evidence have demonstrated that the LRP also can be involved in chylomicron remnant clearance (13, 14, 15, 16, 17, 18, 19, 20) . The LRP has been shown to bind remnants and remnant-like lipoproteins containing excess added apoE. The space of Disse is an environment rich in this apolipoprotein (21) . Thus, remnants could acquire excess apoE and then be recognized by the LRP. Physiological evidence that the LRP is involved in chylomicron remnant clearance in vivo was suggested by the partial inhibition of the clearance of radioactive chylomicrons from the plasma of mice that had been injected with activated -macroglobulin (16, 19) . Although both the LDL receptor and the LRP have been implicated in the uptake of chylomicron remnants, it has been difficult to determine which, if either, plays the dominant role in this process.

The present studies of chylomicron metabolism were conducted in rabbits, since this species has been used extensively in lipoprotein studies. It was previously shown that the liver is responsible for about two-thirds of the uptake of intravenously injected chylomicrons and that the bone marrow also takes up significant amounts (22, 23) . Furthermore, chylomicron catabolism by the liver increased in rabbits when the chylomicrons were incubated with apoE (22) . In addition, plasma cholesterol levels decreased when apoE was infused into cholesterol-fed and Watanabe heritable hyperlipidemic (WHHL) rabbits (24) .

The hyperlipidemia of cholesterol-fed rabbits is quite different from that of WHHL rabbits. High cholesterol diets cause a marked accumulation of -migrating very low density lipoproteins (-VLDL), which consist of VLDL remnants and chylomicron remnants (25, 26) , and a down-regulation of LDL receptors (27, 28, 29, 30, 31) . The hyperlipidemia induced by dietary cholesterol is due to overproduction of lipoproteins and impaired plasma clearance secondary to the down-regulation of LDL receptor expression (27, 32, 33, 34) . In contrast, a genetic deficiency of LDL receptors in WHHL rabbits causes the accumulation of LDL and lesser amounts of VLDL and intermediate density lipoprotein remnant particles (for review, see Refs. 35 and 36).

There are conflicting reports concerning the effect of cholesterol-induced hyperlipidemia on chylomicron catabolism in different species. Chylomicron clearance has been shown to be retarded in cholesterol-fed rabbits and hypothyroid rats (32, 33, 37, 38, 39) but not in cholesterol-fed rats (32) and dogs (40, 41) . It has been reported that chylomicron clearance was normal in WHHL rabbits (42, 43) . However, other studies suggest that chylomicron clearance is retarded in these rabbits (44, 45) .

The present study employs the novel technique of cross-circulation of plasma lipoproteins either between normal and WHHL rabbits or normal and cholesterol-fed rabbits to examine the steps involved in the remnant pathway and to understand the mechanism involved in the development of hyperlipidemia in these rabbits. Cross-circulation eliminates the potential problem of denaturing the fragile chylomicrons and their subsequent uptake by liver Kupffer cells (46) . We demonstrate that chylomicron clearance is impaired in WHHL rabbits and in cholesterol-fed rabbits. In addition, using this technique, we demonstrate that lipoproteins present in the plasma of hyperlipidemic rabbits impair chylomicron clearance. The impairment was due, in part, to competition with endogenously derived lipoproteins containing apoE. We postulate that these lipoproteins inhibit the initial sequestration step in remnant clearance, i.e. the binding of chylomicron remnants to hepatic HSPG.

MATERIALS AND METHODS

Animals and Diets

Preparation of Lipoproteins

Iodination of 9D9 and LRP-515 Immunoglobulins

Plasma Clearance and Tissue Uptake of Radiolabeled Chylomicrons and I-Labeled 9D9 in Normal, Cholesterol-fed, and WHHL Rabbits

For chylomicron clearance studies, the [H]retinol- and [C]cholesterol-labeled chylomicrons were injected into the animals at a dose of 75 mg of triglyceride/kg of body weight. Blood samples and liver biopsies were obtained at designated intervals. The rabbits were euthanized at 40 min by intravenous injection of euthanasia solution (Anthony Products Co., Arcadia, CA, 200 mg of sodium pentobarbital/kg of body weight) followed by bilateral thoracotomy or perfusion fixation (22, 23) . Tissues (liver, bone marrow, spleen, kidney, adrenals, heart, lung, and perinephric fat) were obtained. To determine receptor levels, monoclonal antibodies were injected into the three groups of rabbits at a dose of 25 µg of protein/kg of body weight, and experiments were performed as described above for chylomicrons.

Plasma Clearance and Tissue Uptake in Cross-circulated Rabbits

Plasma Clearance and Tissue Uptake of Lipoproteins in Infusion Studies

The amount of isolated lipoproteins to be injected was calculated to elevate the plasma cholesterol levels of the normal rabbits from a base line of 30-80 mg/dl to 200 mg/dl. This value was chosen because levels in this range were typically obtained in the cross-circulated rabbits. The plasma cholesterol levels were determined just before the injection of the chylomicrons and 20 min after the beginning of the lipoprotein infusion. It was possible in most cases to obtain these levels using the d <1.21 and d <1.02 g/ml fractions and LDL. However, much lower levels were obtained with HDL. Plasma Clearance of Chylomicrons from the d < 1.006 g/mlFraction-To determine the plasma clearance of chylomicrons from the d <1.006 g/ml fraction, plasma samples (0.2-0.5 ml) were overlaid with 0.5-0.8 ml of saline and centrifuged (Beckman tabletop ultracentrifuge, TLA100.2 rotor, 100,000 rpm, 2.5 h, 4 °C), and the top 200 µl and bottom fractions were removed and counted. The density distribution of the radiolabeled chylomicrons mixed with plasma (0.2 ml) was determined by centrifugation in parallel with samples obtained from the rabbits.

Effect of ApoE on Chylomicron Catabolism in Cholesterol-fed Rabbits and in Cross-circulated Pairs of Rabbits

Analysis of Plasma and Tissues

To determine the tissue uptake of the monoclonal antibody I-9D9 and radiolabeled chylomicrons, samples of different tissues were obtained in duplicate, weighed, and counted for I in a counter. The tissues were then digested with 0.5 ml of 6 N KOH, and lipids were extracted into ethanol and hexane as described earlier (22, 23) . In those cases where chylomicrons were injected alone, the tissues were digested and extracted as described (22, 23) .

Determination of Plasma Volume and Tissue Weights

Other Analyses

RESULTS

Chylomicron Metabolism in Normal, Cholesterol-fed, and WHHL Rabbits

Effect of ApoE on Chylomicron Clearance in Cholesterol-fed Rabbits

LDL Receptor and LRP Expression in Normal, Cholesterol-fed, and WHHL Rabbits

These studies demonstrated that cholesterol-fed rabbits expressed lower amounts of LDL receptor activity than did normal rabbits and that WHHL rabbits expressed significantly lower amounts of LDL receptor activity compared with normal and cholesterol-fed rabbits. Even though cholesterol-fed and WHHL rabbits expressed different amounts of LDL receptor activity, they catabolized the radiolabeled chylomicrons to a similar extent, i.e. 50% of the injected dose. This finding suggests that the reduced chylomicron catabolism in these rabbits could only be explained in part by a decreased expression of LDL receptors.

Inhibition of Chylomicron Uptake by Accumulated Plasma Lipoproteins

Cross-circulation of the Blood of Normal and Cholesterol-fed or Normal and WHHL Rabbits

Chylomicron Metabolism in Cross-circulated Normal and Cholesterol-fed Rabbits

Chylomicron Metabolism in Cross-circulated Normal and WHHL Rabbits

Identification and Characterization of Lipoproteins That Compete with Chylomicron Clearance

In contrast, LDL from cholesterol-fed rabbits ( d = 1.02-1.063 g/ml) and from humans ( d = 1.02-1.05 g/ml) did not significantly inhibit the uptake of chylomicrons by the liver. Similarly, human and cholesterol-fed rabbit HDL do not appear to compete with chylomicrons for plasma clearance (), suggesting that the competition was specific for the apoE-enriched HDLand d <1.02 g/ml lipoproteins present in the plasma of the hyperlipidemic rabbits. Therefore, the results obtained both for cross-circulated pairs or lipoprotein-infused rabbits suggest that there are competing lipoproteins in the plasma of hyperlipidemic rabbits and that these lipoproteins rapidly saturate and inhibit remnant clearance from the plasma.

DISCUSSION

The ease of induction of hypercholesterolemia in rabbits by dietary fat and cholesterol suggests that the remnant lipoprotein clearance pathway in this species may be very sensitive to elevated lipoprotein levels. Previously, we demonstrated that the level of apoE may be rate limiting under certain conditions in the rabbit (24) , and clearly apoE is a critical determinant of normal remnant clearance (1, 2, 3) . In addition, hepatic lipase has been shown to be involved in remnant lipoprotein binding to cells in culture (11) and in plasma clearance (6, 7) , and it has been established that the rabbit is deficient in this enzyme (54, 55) . Recently, Fan et al. (56, 57) overexpressed human hepatic lipase in transgenic rabbits and demonstrated a reduced plasma cholesterol level in these rabbits on a normal diet and a reduced tendency to develop diet-induced hypercholesterolemia. Thus, impaired clearance of remnants may reflect abnormalities at one of several points in the pathway, including sequestration in the space of Disse, further lipolytic processing, or receptor-mediated uptake. Other species, such as rats (32) , dogs (40, 41) , and humans (58) , may have remnant pathways that are less sensitive to dietary perturbations, and care must be exercised in trying to extend results obtained in rabbits to other species, including humans.

The studies reported in this paper demonstrate that chylomicron clearance is retarded in both cholesterol-fed and WHHL rabbits. Experiments were performed to define the mechanism(s) responsible for the impaired clearance of remnant lipoproteins. Several possibilities to explain the impaired clearance of chylomicrons were considered.

It was demonstrated that the retarded clearance did not appear to be due primarily to the exchange or transfer of the [C]cholesterol or [H]retinol from the chylomicrons to higher density lipoproteins that are cleared more slowly. Although there was a difference in the die away of the radiolabeled chylomicrons when the whole plasma clearance was compared with that of the d < 1.006 g/ml fraction, the interpretations were similar after the initial time points. It is appreciated that exchange or transfer of these radiolabeled moieties occurs (42, 43) ; however, whole plasma clearance of chylomicrons is considered an appropriate measure of the metabolic activity of these lipoproteins since ultracentrifugal manipulation and time delays necessitated by lipoprotein fractionation can introduce artifacts. Clearly, the whole plasma die away reflected the trends seen with the d < 1.006 g/ml fraction.

The level of apoE on the chylomicrons did not appear to be rate limiting. The addition of excess apoE to the chylomicrons did not result in an accelerated clearance of these lipoproteins from the plasma of the hyperlipidemic animals. As will be discussed later, it appears that the apoE-mediated clearance process is saturated in the hyperlipidemic animals.

The retarded clearance in hyperlipidemic rabbits was not correlated with the expression of hepatic receptors. No significant difference was observed among the rabbits in the level of LRP activity. However, the level of LDL receptor expression differed among the rabbits. The cholesterol-fed rabbits had levels of LDL receptor activity that were lower than those in normal rabbits, but they expressed considerably more LDL receptor activity than was found in the WHHL rabbits. It is reasonable to conclude that the reduced expression of LDL receptors in hyperlipidemic rabbits could result in a reduced capacity of the hepatocytes to take up the remnant lipoproteins. However, since the cholesterol-fed and WHHL rabbits had similar impaired chylomicron clearance but very different levels of LDL receptor activity, the reduced expression of hepatic LDL receptors did not appear to be the primary rate-limiting factor in the reduced clearance of chylomicron remnants in these rabbits.

Consistent with data from the present study is the conclusion that lipoproteins that accumulate in the plasma of cholesterol-fed and WHHL rabbits retard remnant clearance by interfering with an initial rapid phase of clearance. Cross-circulation of normal and cholesterol-fed or normal and WHHL rabbits allowed the rapid infusion of cholesterol-induced or WHHL plasma lipoproteins into the circulation of normal rabbits and allowed the determination of the acute effects of plasma lipoproteins on liver uptake. This obviated criticism of the effects of isolation on lipoprotein composition and function. Furthermore, these studies were completed within 1 h, a short time interval during which major changes in LDL receptor activity would not be expected to play a major role. The rapid influx of the hyperlipidemic plasma during cross-circulation from cholesterol-fed and WHHL rabbits retarded the liver uptake of chylomicrons in normal rabbits. We interpret these results as indicating that the competing lipoproteins saturate the early steps involved in the clearance of chylomicrons ( i.e. sequestration in the space of Disse). It is reasonable to speculate that the apoE-containing remnants rapidly interact with the HSPG in the space of Disse and saturate the initial step in the remnant clearance pathway. We have established that HSPG-remnant interaction is essential for the binding of remnant lipoproteins and facilitates the actual uptake of the lipoproteins, presumably in association with the LRP (8, 9) . This process may be facilitated by the enrichment of the particles with apoE (8, 9) or by the interaction of the remnants with hepatic lipase (6, 7, 11) in the space of Disse.

Canine HDLand remnant lipoproteins competed for chylomicron clearance. However, when comparing the effects of different lipoproteins, it is difficult to know how to calculate the amount to be infused. The ideal approach would be to infuse similar numbers of particles, but this is impossible when comparing very heterogeneous lipoprotein classes such as VLDL or remnants. Therefore, we decided to inject sufficient d <1.21 g/ml, d <1.02 g/ml, and LDL to elevate the plasma cholesterol from a normal level of 30-50 mg/dl to 200 mg/dl. The protocol was designed to mimic the cross-circulation studies ( i.e. infusion of the isolated lipoproteins, a 12-15-min period of equilibration, and completion of the study in 1 h). As shown, the d <1.02 g/ml lipoproteins (remnants and intermediate density lipoproteins) and cholesterol-induced canine lipoproteins containing primarily apoE (HDL) inhibited chylomicron clearance (). These in vivo data confirm previous results obtained in the perfused rat liver, demonstrating that HDLinhibit chylomicron remnant clearance (53) .

In contrast to the inhibition seen with remnant lipoproteins and HDL, LDL did not appear to inhibit liver uptake. Likewise, HDL did not appear to inhibit chylomicron uptake. However, since HDL are less cholesterol-rich lipoproteins, it was difficult to obtain sufficient HDL to raise the plasma cholesterol to 200 mg/dl. Nevertheless, tremendous amounts of HDL were infused and did not appear to affect chylomicron clearance. These results indicate that specific lipoproteins, e.g. apoE-containing and remnant lipoproteins, compete for lipoprotein clearance.

In summary, chylomicron catabolism was markedly retarded in cholesterol-fed and WHHL rabbits. The primary factor for the retarded clearance appears to be competition of the specific plasma lipoproteins that interfere with the clearance step involved in remnant uptake, i.e. saturation of sequestration in the space of Disse. Enrichment of the remnants with apoE may not have enhanced remnant clearance because of impaired access of these lipoproteins to the already saturated binding sites involved in the sequestration phase of clearance.

  
Table: Liver and bone marrow uptake of [C]cholesterol-labeled chylomicrons in the cross-circulated pairs of rabbits

  
Table: Effect of isolated lipoproteins on [C]cholesterol-labeled chylomicron uptake by the liver and bone marrow of normal rabbits

Isolated lipoproteins were infused intravenously into normal rabbits for a period of 5-8 min. Control animals received a saline infusion for 5-8 min. At 20 min after the start of infusion, chylomicrons were injected into these rabbits, and blood samples were collected for an additional 40 min, at which time the animals were euthanized, and tissue samples were obtained (see ``Materials and Methods'').

FOOTNOTES

*

This work was supported in part by American Heart Association Research Grant 90-1327 and by National Institutes of Health Program Project Grant HL 41633. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked `` advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

Current address: Depts. of Pathology and Biochemistry, Medical College of Pennsylvania, Philadelphia, PA 19129.

¶

To whom correspondence should be addressed: Gladstone Institute of Cardiovascular Disease, P. O. Box 419100, San Francisco, CA 94141-9100. Tel.: 415-826-7500; Fax: 415-285-5632.

The abbreviations used are: apoE, apolipoprotein E; HDL, high density lipoproteins; HDL, cholesterol-induced canine lipoproteins containing primarily apoE; HSPG, heparan sulfate proteoglycans; LDL, low density lipoproteins; LRP, LDL receptor-related protein; VLDL, very low density lipoproteins; WHHL, Watanabe heritable hyperlipidemic.

ACKNOWLEDGEMENTS

We gratefully acknowledge Dr. Robert C. Kowal of Brigham and Women's Hospital in Boston for the monoclonal antibody LRP-515; Dr. Karl H. Weisgraber for rabbit apoE; BioTechnology General in Israel for human recombinant apoE; R. Dennis Miranda, Peter A. Lindquist, and Marilyn Hathaway for technical support; Sylvia Richmond for manuscript preparation; Charles Benedict and Tom Rolain for graphics; and Dawn Levy and Lewis DeSimone for editorial assistance. We appreciate the skilled surgical expertise of Peter A. Lindquist, who performed the surgeries for the cross-circulation studies.

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