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PubMed1973

Lymph chylomicron formation during the inhibition of protein synthesis. Studies of chylomicron apoproteins.

The effect of impaired intestinal protein synthesis on chylomicron apoprotein composition was studied in mesenteric lymph fistula rats. Lymph was obtained from animals with impaired protein synthesis given intraperitoneal acetoxycycloheximide (ACH), a potent inhibitor of protein synthesis. Lymph chylomicrons were then isolated by ultracentrifugation and purified on agarose columns. Purified chylomicrons from control and ACH-treated animals were delipidated, and their apoprotein pattern was examined on sodium dodecyl sulfate (SDS) polyacrylamide gels. Because we had previously demonstrated a markedly increased lymph chylomicron size during the inhibition of protein synthesis, it was first necessary to determine whether chylomicron apoprotein composition normally varied with chylomicron size. Chylomicrons of varying sizes were prepared by differential ultracentrifugation, and their apoprotein composition was determined densitometrically on SDS polyacrylamide gels. No significant difference in apoprotein composition was found normally with varying chylomicron size. In contrast, however, chylomicrons from ACH-treated animals showed a 50% decrease in a major apoprotein band with R(1) 0.67. Other chylomicron apoproteins were not decreased as a result of impaired protein synthesis, suggesting differing rates of synthesis of the various chylomicron apoproteins. In vivo incorporation studies of [(3)H]leucine into the various apoproteins of lymph chylomicrons demonstrated that this apoprotein (R(1) 0.67) had the most rapid synthesis rate and suggested that it seemed most affected by impaired intestinal protein synthesis. Immunologic studies indicated that this apoprotein was immunologically related to high-density lipoproteins (HDL) and was present in chylomicrons isolated directly from small intestinal mucosa. These studies demonstrate that impaired intestimal protein synthesis is associated with a deficiency in one of the major chylomicron apoproteins and may in part explain the impaired lipid absorption seen during states of impaired protein synthesis.

Animals↗
PubMed1989

Chylomicron metabolism. Chylomicron uptake by bone marrow in different animal species.

Previously it was shown in rabbits that 20-40% of the injected dose of chylomicrons was cleared from the plasma by perisinusoidal bone marrow macrophages. The present study was undertaken to determine whether the bone marrow of other species also cleared significant amounts of chylomicrons. Canine chylomicrons, labeled in vivo with [14C]cholesterol and [3H] retinol, were injected into marmosets (a small, New World primate), rats, guinea pigs, and dogs. Plasma clearance and tissue uptake of chylomicrons in these species were contrasted with results obtained in rabbits in parallel studies. The chylomicrons were cleared rapidly from the plasma in all animals; the plasma clearance of chylomicrons was faster in rats, guinea pigs, and dogs compared with their clearance from the plasma of rabbits and marmosets. The liver was a major site responsible for the uptake of these lipoproteins in all species. However, as in rabbits, the bone marrow of marmosets accounted for significant levels of chylomicron uptake. The uptake by the marmoset bone marrow ranged from one-fifth to one-half the levels seen in the liver. The marmoset bone marrow also took up chylomicron remnants. Perisinusoidal macrophages protruding through the endothelial cells into the marrow sinuses were responsible for the accumulation of the chylomicrons in the marmoset bone marrow, as determined by electron microscopy. In contrast to marmosets, chylomicron clearance by the bone marrow of rats, guinea pigs, and dogs was much less, and the spleen in rats and guinea pigs took up a large fraction of chylomicrons. The uptake of chylomicrons by the non-human primate (the marmoset), in association with the observation that triglyceride-rich lipoproteins accumulate in bone marrow macrophages in patients with type I, III, or V hyperlipoproteinemia, suggests that in humans the bone marrow may clear chylomicrons from the circulation. It is reasonable to speculate that chylomicrons have a role in the delivery of lipids to the bone marrow as a source of energy and for membrane biosynthesis or in the delivery of fat-soluble vitamins.

Animals↗
PubMed1988

Competition between chylomicrons and their remnants for plasma removal: a study with artificial emulsion models of chylomicrons.

In previous studies, protein-free emulsions of defined lipid composition were shown capable of simulating either the metabolism of chylomicrons (chylomicron-like emulsion) or their remnants (remnant-like emulsion), depending on the content of free, unesterified cholesterol. To validate further the assumption that remnant-like and chylomicron-like emulsion have metabolic pathways in common with their natural counterparts, studies of competition for plasma removal were undertaken: the remnant-like emulsion labeled with [3H]triolein was injected sequentially twice in the carotid arteries of rats to compare the clearance of remnant-like emulsion of the second injection with the first (control). Prior to the second injection, a large bolus of the chylomicron-like emulsion or rat lymph chylomicron was injected, to check the hypothesis that remnant generated from chylomicron-like emulsion or natural chylomicrons could compete with and displace remnant-like emulsion particles from their tissue receptor sites. Experiments were also performed in rats treated with Triton WR-1339, to block the generation of remnants. Results showed that remnants derived from either natural chylomicrons or chylomicron-like emulsion both strongly competed with the remnant-like emulsion. In contrast, when transformation of remnants was prevented by Triton, the undegraded particles of chylomicron-like emulsion or natural chylomicron were unable to compete with or displace remnant-like emulsion from its sites of removal from the plasma. In agreement with plasma clearance data, the hepatic uptake of the remnant-like emulsion was inhibited by the surplus dose of natural chylomicrons. In contrast, the spleen uptake was unaffected by it.

Animals↗
PubMed1996

The role of lipoprotein lipase and apoprotein E in the recognition of chylomicrons and chylomicron remnants by cultured isolated mouse hepatocytes.

Lipoprotein lipase (LPL) has been proposed to play a role in the uptake of chylomicron remnants by hepatocytes by mediating the binding of these lipoproteins to cell-surface glycosaminoglycans and to the low-density-lipoprotein receptor-related protein (LRP). This proposal is based on studies that examined the binding of chylomicrons to HepG2 cells, fibroblasts and Chinese hamster ovary cells in culture, in the presence of large amounts of LPL [Beisiegel (1995) Curr. Opin. Lipidol. 6, 117-122]. We have investigated whether LPL attached to the surface of chylomicrons enhances the binding and uptake of these lipoproteins to isolated hepatocytes maintained in culture. Bovine milk LPL was bound to mouse chylomicrons, double-labelled in vivo with [3H]retinol (in retinyl esters) and with [14C]palmitic acid (in triacylglycerols), collected from the mesenteric lymph of normal mice and from mice lacking the apoprotein E (apo E) gene. Normal chylomicrons (containing apo E) and apo E-free chylomicrons, with or without bound LPL, were incubated with cultured hepatocytes isolated from mice lacking the apo E gene. At 0 degree C LPL did not enhance the binding of the normal or apo E-free chylomicrons by the hepatocytes. When incubations were performed at 37 degrees C the triacylglycerols of normal and apo E-free chylomicrons were hydrolysed by LPL and there was a significant uptake of [14C]fatty acids and [3H]retinol by the hepatocytes. The addition of heparin or lactoferrin, a known inhibitor of hepatic uptake of chylomicron remnants, to the incubation medium inhibited the uptake of [3H]retinol, present in the lipoprotein core, but not the uptake of the [14C]fatty acids. We conclude that: (1) LPL attached to chylomicrons in amounts sufficient to effectively hydrolyse their core triacylglycerols does not enhance the binding of these lipoproteins to the surface of isolated hepatocytes; (2) the recognition and uptake of chylomicrons by hepatocytes requires that these lipoproteins be first hydrolysed by LPL; and (3) the uptake of lipolysed chylomicrons (remnants) by hepatocytes does not require the mediation of apo E.

Animals↗
PubMed1989

Chylomicron-chylomicron remnant clearance by liver and bone marrow in rabbits. Factors that modify tissue-specific uptake.

The metabolism of [14C]cholesterol- and [3H]retinol-labeled chylomicrons obtained from canine thoracic duct or rabbit mesenteric lymph was investigated in normal fasted rabbits. Typically, 70-80% of the chylomicrons injected into the rabbits were cleared from the plasma in 20 min, and their uptake was accounted for principally by the liver and the bone marrow. Surprisingly, the bone marrow was a major site of uptake; the uptake ranged from about half that of the liver to a nearly equal amount. The importance and specificity of chylomicron-chylomicron remnant uptake by the bone marrow were established by demonstrating that (a) bone marrow throughout the body accumulated these lipoproteins, (b) the level of uptake was consistent regardless of how the values were calculated or how the chylomicrons were prepared, (c) the uptake represented specific binding, and (d) radiolabeled intestinal lipoproteins induced in vivo delivered cholesterol and retinol to the marrow. Electron microscopic examination of the rabbit bone marrow established that perisinusoidal macrophages uniquely accounted for the uptake of the chylomicrons. Whereas liver cleared a variety of both triglyceride-rich lipoproteins (chylomicrons, chylomicron remnants, and very low density lipoproteins) and cholesterol-rich lipoproteins (beta-very low density lipoproteins and high density lipoproteins containing apolipoprotein E), bone marrow uptake appeared to be restricted to the triglyceride-rich lipoproteins. More chylomicron remnants (generated in a hepatectomized rabbit) were cleared by the liver than by the bone marrow, and the addition of excess apolipoprotein E to chylomicrons resulted in their preferential uptake by the liver. The role of chylomicron-chylomicron remnant delivery of lipids or lipid-soluble vitamins to rabbit bone marrow is open to speculation, and whether triglyceride-rich lipoprotein uptake occurs to a significant extent in the bone marrow of humans remains to be determined.

Animals↗
PubMed1981

Hepatic uptake of phospholipid-depleted chylomicrons in vivo. Comparison with the uptake of chylomicron remnants.

1. Rats pretreated with Triton WR-1339 to prevent the formation of remnants were injected with [3H]cholesterol-labelled remnants, intact chylomicrons or chylomicrons depleted of most of their surface phospholipids by treatment with phospholipase A2. Within 5 min about 80% of the injected label of remnants and phospholipid-depleted chylomicrons was incorporated into the livers compared with less than 10% of the injected radioactivity of intact chylomicrons. A similar rapid hepatic uptake of radioactivity occurred when rats not pretreated with Triton were injected with [3H]cholesterol-labelled phospholipid-depleted chylomicrons. This rapid hepatic uptake of phospholipid-depleted chylomicrons occurred apparently without any alteration in the apoprotein composition of the particles. 2. The participation of hepatocytes in the uptake of remnants and phospholipid-depleted chylomicrons was examined. Both types of particles were taken up by the hepatocytes. However, small chylomicrons (Sf less than 400) were taken up more efficiently than were large chylomicrons (Sf greater than 400), but neither was taken up as efficiently as the remnants. 3. The results of this study lend support to the hypothesis that phospholipid-depleted chylomicrons and chylomicron remnants are taken up by the liver by a similar mechanism, which depends on the loss of surface phospholipids.

Animals↗
PubMed1978

Composition of proteins of mesenteric lymph chylomicrons in the rat and alterations produced upon exposure of chylomicrons to blood serum and serum proteins.

Protein composition was determined in mesenteric lymph chylomicrons from fat-fed rats. Among the proteins of intermediate molecular weight, apoproteins A-I and the arginine-rich apoprotein accounted for 31% and 4% of the total protein mass, respectively. Apoprotein B and apoprotein A-IV each accounted for about 10% and proteins of low molecular weight (C apoproteins and apoprotein A-II) accounted for most of the remainder. Apoprotein A-I also accounted for more than 30% of the protein mass of mesenteric lymph lipoproteins of density less than 1.006 g/ml ("small chylomicrons") obtained from rats fed glucose. Aproprotein A-I was partially dissociated from chylomicrons during brief ultracentrifugation. Both the arginine-rich apoprotein and the C apoproteins in rat blood serum were transferred to lymph chylomicrons from fat-fed rats during incubation in vitro. Content of arginine-rich apoprotein, determined immunochemically, increased six-fold when chylomicrons were diluted to a final concentration of 500 mg/dl in blood serum. Upon incubation of chylomicrons in equivalent volumes of ultracentrifugal fractions of serum, the increase of the arginine-rich apoprotein was: very low density lipoproteins, 1.5-fold; high density lipoproteins, 1.8-fold; density fraction greater than 1.006 g/ml, 5.0-fold; density fraction greater than 1.21 g/ml, 11-fold. Content of apoprotein A-I, also determined immunochemically, was not altered appreciably by exposure to serum or its ultracentrifugal fractions, whereas content of C apoproteins, estimated from intensity of staining of the low molecular weight protein component in polyacrylamide gel electropherograms, increased in all cases except for the density fraction greater than 1.21 g/ml. The fractional content of apoprotein A-I in the protein of chylomicrons fell after incubation, whereas that of the arginine-rich apoprotein remained constant or rose substantially. The fractional content of apoprotein A-IV in chylomicron-protein tended to follow that of apoprotein A-I, as judged from polyacrylamide gel electropherograms. Transfer of the arginine-rich and C apoproteins to chylomicrons from blood serum was directly related to the volume of serum in which the chylomicrons were diluted and occurred rapidly at room temperature or at 4 degrees C.

Animals↗
PubMed1998

Effects of chylomicrons and chylomicron remnants on endothelium-dependent relaxation of rat aorta.

The effects of chylomicrons and chylomicron remnants on endothelium-dependent relaxation of rat aorta were studied in vitro. Chylomicrons and chylomicron remnants were prepared in vivo. Aortic rings were incubated with the lipoproteins for 45 min before the vessels were constricted with phenylephrine and concentration relaxation response curves constructed to carbachol, ATP, A23187 and S-nitroso-N-acetylpenicillamine. Maximum % relaxations to carbachol were significantly reduced by both chylomicrons and chylomicron remnants but responses to ATP and S-nitroso-N-acetylpenicillamine were unaffected. In addition, chylomicrons significantly inhibited A23187-induced relaxation, causing an increase in the EC50 value. Chylomicron remnants cause selective inhibition of carbachol-induced relaxation suggesting an action at the receptor or G protein-coupled component of the receptor-mediated activation of the L-arginine-nitric oxide pathway. Chylomicrons appear to be less selective in their inhibition of the endothelium-dependent relaxation. This study demonstrates that lipoprotein particles of dietary origin may cause endothelial cell dysfunction.

Adenosine Triphosphate↗
PubMed1996

Modification of the fatty acid composition of dietary oils and fats on incorporation into chylomicrons and chylomicron remnants.

Possible changes in the fatty acid composition of dietary fats and oils which might occur during digestion, absorption and formation of chylomicrons and chylomicron remnants were investigated. Chylomicrons were collected from the thoracic duct of rats tube-fed with olive, maize, palm or fish oil or butter fat, and their fatty acid composition was determined and compared with that of their parent lipids. In turn, these lipoproteins were converted to chylomicron remnants in functionally hepatectomized rats and their composition re-determined. The predominant fatty acids in each of the oils and fats also predominated in their respective chylomicrons, but their proportions were reduced during the processes leading to their formation. Endogenous contributions of linoleic, eicosapentaenoic, and docosahexaenoic acids were particularly noted when these fatty acids were not well-represented in the original oils and fats, suggesting that they may be obligatory constituents in the formation of chylomicrons. The conversion of chylomicrons to remnants further attenuated the extremes in fatty acid composition of the dietary oils and fats. These results indicate that following an acute intake of oil or fat, the resulting chylomicrons and chylomicron remnants presented to the tissues contain a more balanced distribution of saturated, mono- and polyunsaturated fatty acids than the oils and fats from which they were derived.

Animals↗
PubMed2000

Postprandial chylomicrons and VLDLs in severe hypertriacylglycerolemia are lowered more effectively than are chylomicron remnants after treatment with n-3 fatty acids.

BACKGROUND: n-3 Fatty acids lower plasma triacylglycerols not only in the fasting state but also in the postprandial state. However, it is not known whether chylomicrons, chylomicron remnants, and VLDLs are all affected equally or whether some lipoprotein species are lowered preferentially. OBJECTIVE: Lipoproteins, including large and small chylomicron remnants, were determined specifically with the aid of a newly developed method involving a combination of size-exclusion chromatography and fluorometric determination of retinyl palmitate, which served as a marker for exogenous fat. DESIGN: Twelve hypertriacylglycerolemic men were treated for 6 wk with 4 capsules containing 85% fish-oil concentrate/d; each capsule contained 850 mg n-3 fatty acid ethyl esters (49.1% eicosapentaenoic acid by wt and 32.2% docosahexaenoic acid by wt). Oral-fat-tolerance tests were performed before and after the treatment. Blood samples were drawn in the fasting state and until 8 h postprandially. RESULTS: Treatment with n-3 fatty acids reduced the fasting VLDL-triacylglycerol concentration by 44% (P < 0.05) and postprandial chylomicrons and VLDLs at 4, 6, and 8 h (P < 0.05) by 49-64% and 36-43%, respectively. Chylomicron remnants were reduced only in the late postprandial phase: large chylomicron remnants by 19% at 6 h and by 43% at 8 h (P < 0.05) and small chylomicron remnants by 31% at 8 h (P < 0.05). CONCLUSION: n-3 Fatty acids effectively lower chylomicrons and VLDLs, but their effect on chylomicron remnants was observed only in the late postprandial phase.

Adult↗
PubMed2004

Metabolism of chylomicrons in patients with congenital lipoatrophic diabetes: a study with emulsion models of chylomicrons.

BACKGROUND: Lipoatrophic diabetes is characterized by the near absence of adipose tissue and the presence of insulin-resistant diabetes. Fasting hypertriglyceridaemia and increased postprandial lipidaemia are also present, but the metabolism of chylomicrons, the triglyceride-rich lipoproteins in the circulation that carry the dietary fats absorbed by the intestine, was not specifically investigated. Because both the activity of insulin-dependent lipoprotein lipase that catalyses the chylomicron lipolysis and the storage of the lipolysis products are affected in the disease, it is important to evaluate how those changes may ultimately affect the chylomicron lipolysis and removal of chylomicron remnants from the circulation. OBJECTIVE: The aim of the study was to evaluate the chylomicron intravascular metabolism in patients with lipoatrophic diabetes. PATIENTS: Six patients with lipoatrophic diabetes (four females, two males) aged 22.2 +/- 4.4 years, with body mass index (BMI) 21.6 +/- 3.6 kg/m(2), were compared with 12 healthy control subjects (seven females, five males) aged 24.3 +/- 2.1 years with BMI 22.5 +/- 2.7 kg/m(2). MEASUREMENTS: The plasma kinetics of intravenously injected chylomicron-like emulsions labelled with (3)H-triglycerides ((3)H-TG) and with (14)C-cholesteryl esters ((14)C-CE) were determined, the former tracing the chylomicron lipolysis by lipoprotein lipase and the latter the removal of chylomicron remnants from the plasma. RESULTS: Triglyceride values (8.3 +/- 9.2 mmol/l) in the patients were higher (P < 0.005) and high density lipoprotein (HDL) cholesterol values (0.8 +/- 0.2 mmol/l) lower (P < 0.0005) than in controls (0.7 +/- 0.2 and 1.3 +/- 0.4 mmol/l, respectively) whereas total cholesterol, apoprotein B (apo B) and apo A1 were similar. The fractional clearance rate (FCR, in min(-1)) of (3)H-TG was 0.014 +/- 0.016 and the FCR of (14)C-CE was 0.008 +/- 0.012 in the patients and 0.046 +/- 0.024 and 0.024 +/- 0.012 in the controls, respectively (P < 0.05). Thus FCRs of both emulsion labels were markedly reduced in the patients, indicating that lipolysis and remnant removal were diminished. Diminished remnant removal may be due to either deficient lipolysis or deficient removal mechanisms. CONCLUSION: The metabolism of chylomicrons tested by the emulsion method is impaired in lipoatrophic diabetes.

Adult↗
PubMed1987

The effect of thermally oxidized soya bean oil on metabolism of chylomicrons. Increased uptake and degradation of oxidized chylomicrons in cultured mouse macrophages.

Oral administration of thermally oxidized soya bean oil (TO) increased the level of lipid peroxides in human plasma, mainly in chylomicrons. No changes were observed after fresh oil (FO) intake. Human chylomicrons obtained after TO ingestion were rich in lipid peroxides and degraded more rapidly by cultured mouse macrophages than chylomicrons after FO. The uptake of TO chylomicrons by macrophages occurred via a saturable process and was partially inhibited by beta-very low density lipoprotein as well as by acetyl-low density lipoprotein and fucoidin. A 48-h incubation of macrophages with TO chylomicrons caused a 10-fold higher accumulation of cholesterol ester mass in the cells than the incubation with FO chylomicrons. These studies suggest that chylomicrons containing lipid peroxides may be taken up by mouse macrophages by mediation of beta-VLDL receptor as well as by acetyl-LDL receptor, and show a potential pathway by which chylomicrons obtained after ingestion of heated oil could contribute to accumulation of cholesterol esters in macrophages.

Adult↗
PubMed1995

Postprandial intestinal-derived chylomicron and chylomicron remnants in essential hypertensive patients before and after prolonged captopril therapy.

The metabolism of the postprandial intestinal-derived lipoproteins, chylomicron and chylomicron remnants, is not known in patients with essential hypertension. After a fat meal, using the vitamin A test as a marker, retinyl palmitate was measured in the total plasma, chylomicron, and chylomicron remnant fractions in 14 untreated nondiabetic essential hypertensive patients with normal fasting lipids and lipoproteins. The vitamin A fat loading test was repeated in eight hypertensive patients after 3 months of captopril therapy. Fifteen matched normotensive subjects were used as controls. The untreated essential hypertensive patients had significantly higher chylomicron fraction concentration curves (AUC 17,469 +/- 2553 micrograms/L/h) P < .001 compared with the control group (AUC 13,208 +/- 1245 micrograms/L/h), by two-way analysis of variance with repeated measurements. After 3 months of captopril therapy, the chylomicron fraction (AUC 9701 +/- 1566 micrograms/L/h), and chylomicron remnants fraction (AUC 3487 +/- 580 micrograms/L/h) were much lower (P < .001) than before captopril therapy. Oral glucose tolerance tests were borderline in five of the eight hypertensives before captopril treatment but returned to normal after 3 months of therapy. In summary, postprandial intestinal-derived lipoprotein metabolism is altered in essential hypertensive patients. Captopril therapy caused significant improvement in the postprandial chylomicron metabolism.

Captopril↗
PubMed1995

Uptake of chylomicron remnants and hepatic lipase-treated chylomicrons by a non-transformed murine hepatocyte cell line in culture.

AML 12 is a recently established differentiated, non-transformed hepatocyte cell line derived from mice transgenic for transforming growth factor alpha (Wu et al. (1994) Proc. Natl. Acad. Sci. 91, 674-678). The ability of these cells to take up [3H]cholesterol-labeled in vivo-generated chylomicron remnants, as well as [3H]cholesterol-labeled chylomicrons treated with hepatic lipase in vitro was investigated. Both types of lipoprotein particles were taken up by the AML hepatocytes at a much faster rate than intact chylomicrons, and in a saturable and specific manner. Chylomicrons treated with hepatic lipase in vitro competed with in vivo-generated chylomicron remnants for uptake by the AML hepatocytes, and the uptake of both types of lipoproteins was inhibited by lactoferrin, suggesting that they share the same process of cellular recognition and uptake. It is suggested that hepatic lipase-treated chylomicrons may be valuable in studies aimed at gaining a better understanding of the processes involved in the hepatic recognition and uptake of chylomicron remnants. AML hepatocytes, which can be maintained as replicating, untransformed, and differentiated under standard culture conditions, may be useful and practical for such studies.

Animals↗
PubMed1978

Comparison of the metabolism of chylomicrons and chylomicron remnants by the perfused liver.

1. The hepatic metabolism of chylomicrons and chylomicron remnants was compared after adding approximately equal numbers of each lipoprotein particle to the perfusate of isolated livers. 2. At least 40% of the added remnants were metabolized by the liver compared with less than 3% for chylomicrons. 3. There was significantly more net removal of labelled remnants than of chylomicrons by the liver. 4. A greater proportion of labelled cholesterol than of labelled triacylglycerol fatty acids was transferred to the liver from each lipoprotein. 5. Cholesteryl esters of remnants were hydrolysed to triacylglycerol fatty lipoprotein. 5. Cholesteryl esters of remnants were hydrolysed to triacylglycerol fatty acids of remnants were oxidized to CO2 more extensively than those of chylomicrons. 6. There was greater oxidation of remnant glycerolipic [(1(-14)C]oleate than of glycerolipid [1(-14)C]palmitate. 7. A large fraction of the fatty acids of remnants, but not of chylomicrons, was transferred to phospholipids, which were released by the liver in a lipoprotein of relative density less than 1.006. 8. Label from remnants, but not from chylomicrons, was found in lipoproteins of relative density greater than 1.006, which were not released during perfusion but could be flushed out from the liver at the end of perfusion.

Animals↗
PubMed1991

Chylomicron-remnant clearance in homozygote and heterozygote Watanabe-heritable-hyperlipidaemic rabbits is defective. Lack of evidence for an independent chylomicron-remnant receptor.

Lymph chylomicrons radiolabelled in triacylglycerol and cholesteryl ester were injected into control and Watanabe heritable-hyperlipidaemic (WHHL) rabbits. Clearance of chylomicrons was slower in heterozygote and homozygote WHHL rabbits. Slower remnant clearance in WHHL rabbits was confirmed by monitoring the clearance from plasma of preformed chylomicron remnants. Use of chylomicron-like lipid emulsions injected into control and WHHL rabbits also confirmed the defect in remnant clearance in heterozygote WHHL and homozygote WHHL groups. Clearance from plasma of emulsion triolein was delayed in both WHHL groups compared with controls, owing to slower remnant clearance. The clearance from plasma of radioiodinated rabbit low-density lipoproteins (LDL) in heterozygote WHHL rabbits was the same as control rabbits. Defective chylomicron-remnant removal but normal LDL clearance in the heterozygote WHHL corresponded to elevated concentrations of plasma triacylglycerol and normal concentrations of plasma cholesterol. Receptor versus non-receptor clearances of chylomicron remnants were studied by comparing the clearance of emulsions with and without unesterified cholesterol respectively. Unlike control rabbits, there were no significant differences in the clearances of the two emulsion types in either the homozygote or heterozygote WHHL rabbits, indicating that the apolipoprotein-B100/E receptor is the primary route for clearance of chylomicron remnants from plasma.

Animals↗
PubMed1995

Lipoprotein lipase enhances removal of chylomicrons and chylomicron remnants by the perfused rat liver.

Lipoprotein lipase has been found to efficiently mediate binding of lipoproteins to cell surfaces and to the low density lipoprotein (LDL) receptor-related protein (LRP) under cell culture conditions (Beisiegel et al. 1991. Proc. Natl. Acad. Sci. USA. 88: 8242-8346). This supports the previously proposed idea that the lipase could have a role in receptor-mediated uptake of chylomicron remnants in the liver. We have investigated the effects of lipoprotein lipase on the clearance of chylomicrons during perfusions of rat livers. The chylomicrons were doubly labeled in vivo with [14C]retinol (in retinyl esters) and with [3H]oleic acid (in triacylglycerols) and were collected from lymph. In the absence of any lipase the clearance of chylomicron label from the perfusion medium was slow. Addition of lipoprotein lipase caused lipolysis of chylomicron triacylglycerols as evidenced by increased levels of 14C-labeled fatty acids in the perfusate. Simultaneously, the level of [14C]retinyl esters in the perfusate decreased dramatically, indicating core-particle removal. Similar effects were seen with an unrelated lipase from Pseudomonas fluorescens. To discriminate between the effects of lipolysis and a true liganding effect of the lipoprotein lipase protein, the active site inhibitors tetrahydrolipstatinR and hexadecylsulfonylfluoride were used to reduce or totally inhibit the catalytical activity. With lipase covalently inhibited by the latter inhibitor, lipolysis during perfusions was low or absent. Nonetheless, the inhibited enzyme had a clear effect on the removal of chylomicrons by the liver. With 1.2 micrograms of inhibited lipase/ml perfusate, about 70% of the core label had been removed after 15 min as compared to about 20% in perfusions without lipase. With identical amounts of active lipoprotein lipase protein, more than 90% of the label was removed. We conclude that any lipase causing lipolysis of chylomicrons can stimulate their clearance by the liver, but that lipoprotein lipase has an additional effect on the removal, which is not dependent on its catalytic activity.

Animals↗
PubMed1994

Acceleration of uptake of LDL but not chylomicrons or chylomicron remnants by cells that secrete apoE and hepatic lipase.

ApoE is a ligand for the low density lipoprotein (LDL) receptor as well as for the LDL receptor-related protein (LRP). The enzyme hepatic lipase (HL) may also affect the uptake of lipoproteins by modifying their composition. We have tested the hypothesis that hepatic lipase and apoE can function as co-factors to alter the rate of lipoprotein uptake. Chinese hamster ovary (CHO) cells were transfected with cDNAs for rat hepatic lipase, human apoE or both HL and apoE. The secreted recombinant proteins were thoroughly characterized and had properties identical to the native proteins. Hepatic lipase and apoE were secreted at 0.17 and 1.25 micrograms/mg cell protein per hour, rates comparable to those in normal liver. 125I-labeled LDL, chylomicron remnants, or chylomicrons were added to media at concentrations near their Kd. In cells that secreted either apoE or hepatic lipase, or both apoE and hepatic lipase, LDL binding was significantly greater than with control cells (2.2-, 2-, 2-fold greater, respectively). Similar enhancement of LDL degradation was observed. In the presence of anti-LDL receptor antibodies, these values were reduced to control levels; thus, the enhanced uptake was mediated by the LDL receptor and not the LRP. The amount of LDL receptor protein, as judged by Western blotting, was similar in the various cell types. Incubation of control CHO cells with media from secreting transfected cells also increased the uptake of 125I-labeled LDL. Kinetic studies indicated that, in apoE-secreting cells, increased LDL binding is associated with a lower Kd and an unchanged Vmax as compared to the control cells; furthermore, when LDL were reisolated by column chromatography (but not by ultracentrifugation) from the incubations where apoE was being secreted, apoE was identified adherent to the LDL particles. Together, these results suggest that the effect is due to alteration of the lipoprotein and not the cell. In contrast, the uptake of 125I-labeled chylomicron remnants, and 125I-labeled chylomicrons was not greater in the transfected cells. Thus, in the amounts secreted by these cells, hepatic lipase and apoE do not convert chylomicrons to chylomicron remnants or alter the uptake of chylomicron remnants by either the LDL receptor or the LRP. The enhancement of LDL removal in cells that secrete hepatic lipase or apoE may help determine the amount of LDL removed by a particular tissue.

Animals↗