Postprandial dyslipidaemia in a nutshell: food for thought.
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Diet, Atherogenic↗
Biomedical subjects
T G Redgrave
Publications and source records attributed to T G Redgrave.
Sterol side chain length and structure affect the clearance of chylomicron-like lipid emulsions in rats and mice.
In previous work we found that sterols such as cholesterol were essential for physiological plasma clearance of lipid emulsions mimicking the structure of mammalian triglyceride-rich lipoproteins. In the present study we compared the clearances of emulsions prepared with sterols of varying alkyl chain length (straight chains, n-C3 to n-C7, or branched chains, i-C5 to i-C10) at the C-17 position. Our studies show that the length of the alkyl chain at the C-17 position of sterols markedly affects the removal of remnant particles from the plasma of rats traced by emulsion cholesteryl oleate label. An alkyl chain of 7 carbons or more was needed for normal remnant clearance. Straight and branched chains of similar length were cleared similarly, showing that the presence of a branch at the end of the alkyl chain had no effect on remnant clearance. For side chains of 7 carbons or less, substitution of sterols with an unsaturation in the alkyl chain close to the terminal carbon markedly decreased the clearance of remnants. Triolein label was used to estimate lipolysis of the injected emulsions. Lipolysis was little affected by the structure of the sterol side chain, except that lipolysis was markedly higher with emulsions containing sterols with an alkyl chain having 4 carbon atoms (n-C4) or with an unsaturation in the 4 carbon alkyl chain. We conclude that the length of the alkyl side chain is an important element in the essentiality of cholesterol as a regulator of metabolism of lipid emulsion models of triglyceride-rich lipoproteins.
Animals↗
A 13CO2 breath test to assess the metabolism of triglyceride-rich lipoprotein remnants in mice.
Remnant-like emulsions were prepared with lipid compositions similar to remnants derived from triacylglycerol-rich lipoproteins. When injected into the bloodstream of conscious mice the remnant-like emulsions labeled with cholesteryl[13C]oleate were metabolized in the liver and the appearance of 13CO2 in the breath was measured. In control mice injected with remnant-like emulsions labeled with cholesteryl[13C]oleate, enrichment of 13CO2 in the breath peaked at 45 min and then decreased markedly by 3 h. In apoE-deficient (-/-) mice no enrichment was found and in low density lipoprotein receptor (LDLr)-deficient (-/-) mice the appearance of 13CO2 in the breath was markedly decreased. These findings were consistent with the ability of the breath test to detect defects in remnant metabolism. The breath test was useful in detecting a defect in remnant metabolism in LDLr heterozygote (+/-) mice, in which the appearance of 13CO2 in the breath was less by 45 min but remained elevated for the duration of the experiment when compared with control mice. In hepatic lipase-deficient (-/-) mice no defect in remnant metabolism was found. Under fasting conditions, the enrichment of 13CO2 in the breath after injection of emulsion was markedly increased when compared with fed mice, indicating that the metabolism of the injected remnant-like emulsion was probably competed for by post-prandial particles under fed conditions. Our findings show that a 13C breath test can be used to assess the metabolism of remnants. The test provides a useful and sensitive method for non-invasive testing of remnant metabolism in experimental animals.
Animals↗
Chylomicron remnant uptake is regulated by the expression and function of heparan sulfate proteoglycan in hepatocytes.
Chylomicron remnants transport cholesterol from the intestine, and are removed from the circulation principally by the liver. While hepatic receptors, including the low density lipoprotein (LDL) receptor account for endocytosis, heparan sulfate proteoglycans (HSPG) participate in the initial binding of remnants to liver cells. To explore the interactions between HSPG and endocytosis of remnants, in the present study the expression of HSPG was inhibited in HepG2 cells transfected by a synthetic antisense oligodeoxynucleotide SYN5. Immunofluorescent staining by a monoclonal anti-syndecan antibody showed significant reduction in the expression of syndecan in SYN5-treated cells compared with control cells. Remnant binding decreased by about 50-70% in SYN5-transfected cells. Monoclonal antibodies to either heparan sulphate or the LDL receptor decreased binding by about 60-65%. The glycosylation inhibitor beta-nitrophenylxylopyranoside inhibited remnant uptake by 25%, whereas 4-nitrophenyl-beta-D-galactopyranoside had no effect on remnant binding. Heparinase completely abolished binding at appropriate concentrations. Heparitinase was less effective than hep arinase in inhibiting remnant binding. Suramin completely abolished the remnant binding. Poly-arginine, poly-lysine, and protamine all reduced remnant uptake by the cells, as did polybrene, a synthetic polycation, suggesting a role of cation-anion interactions in remnant binding. Brefeldin A, colchicine, and monensin caused the fluorescence associated with remnants to persist within the cells, confirming that blockers of tubulovesicular processes and Golgi function inhibit the intracellular transport and degradation of the remnants. Our results show that remnant binding to liver cells depends on the LDL receptor, on the expression of HSPG core proteins, and on the functionality of heparan sulfate in HSPG.
Animals↗
Effect of the ACAT inhibitor CL 277,082 on apolipoprotein B48 transport in mesenteric lymph and on plasma clearance of chylomicrons and remnants.
Inhibitors of acyl CoA:cholesterol acyltransferase (ACAT) activity previously have been found to decrease the absorption of cholesterol and to be effective antiatherosclerotic agents. Effects on chylomicron (CM) transport could contribute to these effects. No previous study has examined the effect of inhibition of ACAT activity on the intestinal lymph output of apolipoprotein (apo) B48 or on the clearance from plasma of lymph CM. In this study, we selected 2,4-difluoro-phenyl-N[[4-(2,2-dimethylpropyl)phenyl]methyl]-N-( hepthyl)urea (CL 277,082) to inhibit intestinal ACAT activity and measured its effects on the output of lipids and apo B48 in intestinal lymph. Compared with control untreated rats, treatment with CL 277,082 decreased the lymph outputs of apo B48 and triglyceride. Associated with the effects on transport, the lymph CM were smaller in diameter in rats treated with CL 277,082. The unesterified cholesterol content of lymph CM was markedly increased and the cholesteryl ester (CE) content was decreased. The contents of triglyceride were decreased and phospholipid was increased. Labeled CM were prepared by feeding donor rats with a test meal containing 3H-cholesterol and 14C-fatty acid. Traced by the CE label in lymph CM in both control rats and rats treated with CL 277,082, the remnants derived after intravenous injection of CM from rats treated with CL 277,082 were cleared significantly more slowly than CM from untreated rats. Moreover, less CE label was recovered in the livers of both groups of rats after injection of CM from rats treated with CL 277,082. Recovery in the spleen was significantly higher in recipient rats injected with CM from rats treated with CL 277,082 when compared with injections of CM obtained from untreated rats. We conclude that the metabolism of CM is affected by treatment with CL 277,082, partly due to the changes in lymph CM composition and partly due to other effects on the recipient rat.
Animals↗
Vasoactive mediators affect the clearance of lipids from emulsion models of plasma lipoproteins in rats.
We wished to establish whether the haemodynamic changes accompanying alterations in blood pressure exert a direct effect on clearance of chylomicron-like emulsions. N-Nitro-L-arginine (NOLA) and endothelin-1 were used to increase the blood pressure of normotensive rats, sodium nitroprusside (NP) and calcitonin gene-related peptide (CGRP) were used to decrease the blood pressure of spontaneously hypertensive rats (SHR). The lipid emulsions contained radiolabeled triolein (TO) and cholesteryl oleate (CO) to trace plasma clearances. NP and CGRP enhanced TO clearance in the SHR but slowed the rate of CO clearance. NOLA in normotensive rats clearly slowed the rate of TO removal and also retarded CO clearance, whereas with endothelin-1 TO clearance remained unaffected and CO removal was markedly slowed. The effects on TO clearance are consistent with changes in arteriolar resistance regulating access of emulsion particles to lipoprotein lipase on the endothelial cells of capillaries in muscle and adipose tissue. The changes in CO removal rate are more difficult to interpret because factors determining hepatic blood flow are complex. The results suggest that haemodynamic changes potentially affect circulation times of various lipoprotein species in the plasma, with probable consequences in relation to atherogenesis.
Animals↗
Receptor-ligand interactions in the hepatic uptake of chylomicron remnants studied with genetically manipulated mice.
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Animals↗
Effects of particle size and number on the plasma clearance of chylomicrons and remnants.
Lymph chylomicrons of different sizes are known to be cleared at different rates, but the underlying mechanism for this effect has not been resolved. To investigate the differences in clearance rates between small and large particles, chylomicron-like lipid emulsions labeled with radioactive triolein and cholesteryl oleate were injected into conscious rats. The clearance from plasma of small emulsion particles was significantly slower than large when equal lipid masses of small and large particles were injected. Similar results were obtained in clearance studies with lymph chylomicrons. When equal numbers of either small or large emulsion particles were injected into rats, the clearance of the triolein label from large particles was significantly slower than small particles but no significant difference was found in the clearance of the remnants (traced by the cholesteryl oleate label) derived from small and large particles. However, when increased numbers of either small or large particles were injected, the clearances of emulsion triolein and remnants were significantly decreased. Larger particles were found to be lipolyzed significantly less than small. Simultaneous injections showed competition for removal of large and small particles, suggesting competition for a common, saturable removal process. Our findings provide evidence that particle number and size are determinants of the rates of plasma clearance of the triglyceride-rich lipoproteins and the results are consistent with a saturable process. Our data also show that particle number is more important than size and higher numbers of particles markedly affect the clearance of triglyceride-rich lipoproteins. However particle uptake by the liver is not sensitive to remnant size.
Animals↗
Intracellular localization and metabolism of chylomicron remnants in the livers of low density lipoprotein receptor-deficient mice and apoE-deficient mice. Evidence for slow metabolism via an alternative apoE-dependent pathway.
The metabolism of chylomicron remnants in mice deficient in low density lipoprotein receptor (LDLr) or apolipoprotein E (apoE) was compared with that of control C57BL/6J mice. Mice were injected intravenously with chylomicron-like emulsions labeled with radioactive lipids. Blood samples were taken at fixed time intervals from the retro-orbital sinus, and clearance rates of the lipoproteins were assessed from the decline in plasma radioactivities. To follow the intracellular pathway of remnants in the liver, emulsions labeled with a fluorescent cholesteryl ester (BODIPY) were injected, and liver sections were processed and assayed by laser confocal microscopy. Catabolism of remnant cholesteryl esters was assessed by injecting emulsions labeled with cholesteryl[1-14C]oleate and measuring the expired CO2 from each animal. In apoE-deficient mice, remnant removal from plasma was totally impeded, while the clearance of remnants in LDLr-deficient mice was similar to that in C57BL/6J control mice. The confocal micrographs of livers 20 min after injection of fluorescent chylomicron-like emulsions showed evenly distributed fluorescent particles in the hepatocytes from control mice. In contrast, the fluorescent particles were mainly located in sinusoidal spaces in LDLr-deficient mice. Three hours after injection the livers from control mice showed few fluorescent particles, indicating that remnants have been catabolized, while the sections from LDLr-deficient mice were still highly fluorescent. Micrographs from apoE-deficient mice showed no fluorescent particles in the liver at any time after injection. Measurement of expired radioactive CO2 after injection of emulsions labeled in the fatty acid moiety of cholesteryl oleate indicated that remnant metabolism was slower in the LDLr-deficient mice and essentially nil in the apoE-deficient mice. Control mice had expired 50% of the injected label by 3 h after injection. We conclude that under normal circumstances, chylomicron remnants are rapidly internalized by LDLr and catabolized in hepatocytes, with a critical requirement for apoE. When LDLr is absent, remnants are taken up by a second apoE-dependent pathway, first to the sinusoidal space of the liver, with subsequent slow endocytosis and slow catabolism. Hepatic clearance via this second pathway is increased by heparin, inhibited by lactoferrin, heparinase, and suramin, and down-regulated by feeding a high fat diet.
Animals↗
The ontogeny of apolipoprotein expression in rat liver. mRNA levels in developing liver and cultured fetal rat hepatocytes.
The pattern of apolipoprotein (apo) A-I, A-IV and E expression in developing rat liver was established by determining steady-state levels of the respective mRNAs. Apo A-I and A-IV altered in a coordinate fashion; the transcripts were detected from day 13 of gestation, whereas apo E was first detected on day 19 of gestation. Apo A-I and A-IV mRNA levels increased with developmental age until day 19, then declined until birth, after which they increased. In contrast, apo E mRNA levels progressively increased from day-13 gestation until 3 days postnatal at which time it reached adult levels. In cultured hepatocytes established from immature (15-day gestation) and near-term (19-day gestation) fetuses the difference in regulation between apo A-I and A-IV and apo E was also observed. In 3-day-old fetal hepatocyte cultures established from 19-day gestation rats, dexamethasone, insulin, thyroxine and glucagon each substantially increased levels of apo A-I and A-IV mRNA but markedly decreased apo E mRNA. Thus fetal and adult hepatocytes respond similarly to the hormones tested with respect to apolipoprotein expression. Unexpectedly, 15-day gestation hepatocytes expressed apo E in culture, even without hormone supplementation. The discrepancy between in vivo and in vitro data suggests that, in the fetus, apo E expression may be suppressed by high levels of circulating steroid, insulin and thyroxine and that establishment of the hepatocytes in culture removes the inhibition, thereby inducing apo E expression in these immature cells. The data are also consistent with the view that the same group of hormones may be responsible for regulating levels of apo A-I and A-IV in the perinatal period. Both apolipoproteins progressively increase as the fetus reaches term at a time when these hormones which induce their expression are also increasing.
Age Factors↗
Intestinal absorption and lymphatic transport of eicosapentaenoic (EPA), docosahexaenoic (DHA), and decanoic acids: dependence on intramolecular triacylglycerol structure.
We compared the absorption of eicosapentaenoic (EPA, 20:5n-3), docosahexaenoic (DHA, 22:6n-3), and decanoic acids in mesenteric lymph duct-cannulated rats following intragastric administration of two oils with different intramolecular triacylglycerol structures. One oil had a specific triacylglycerol structure with EPA and DHA located in the sn-2 position and decanoic acid in the sn-1 and sn-3 positions (specific M-n3-M) whereas the other oil had a random fatty acid distribution (random M-n3-M). The mol% (mol/100 mol total fatty acids) of fatty acids in the two oils was similar, with approximately 66 mol% of decanoic acid and 22 mol% of EPA and DHA. The lymphatic transport (microgram/min) of EPA and DHA as well as the mol% in the total lymph lipids were significantly (both P < 0.01) increased following intragastric administration of specific M-n3-M compared with random M-n3-M. The mol% of decanoic acid in the total lymph lipids was significantly (P < 0.01) higher after random M-n3-M compared with specific M-n3-M but the transport (microgram/min) of decanoic acid was not significantly different. We conclude that under our experimental conditions specific M-n3-M with EPA and DHA predominantly in the sn-2 position of the triacylglycerols was a more readily absorbed source of EPA and DHA and in this context should be investigated further for the potential use in clinical nutrition.
Animals↗
Kinetics and uptake in vivo of oxidatively modified lymph chylomicrons.
The metabolism of oxidized chylomicrons (ox-CMs) was investigated in vivo. CMs from rats fed corn, linseed, or fish oil were oxidized by incubation with 2,2'-azobis(2-amidinopropane)hydrochloride (AAPH) or sodium hypochlorite (NaOCl). Oxidized CMs had a rapid phase of clearance, followed by a slow phase. Clearance of ox-CMs was decreased for corn oil but increased for linseed and fish oil particles. Differences in rats of uptake between CM types or treatment were independent of the rate of remnant formation, but were instead a consequence of decreased clearance. A greater triglyceride-to-cholesteryl ester ratio in liver suggested that there was less lipolysis of ox-CM triglyceride prior to uptake. Hepatic uptake of ox-CMs was decreased, whereas there was increased uptake in spleen. However, the uptake by Kupffer cells of ox-CMs was 43% of total liver uptake after AAPH treatment and 59% after NaOCl treatment, compared with 21% for control CMs. Collectively, our data show that oxidation can have differential effects on the rate of clearance of CMs and that ox-CMs are preferentially cleared by the reticuloendothelial system.
Amidines↗
Features of cholesterol structure that regulate the clearance of chylomicron-like lipid emulsions.
Cholesterol is an absolute requirement for the clearance from plasma of the remnants of triglyceride-rich lipoproteins. Our laboratory previously established that cholesterol was essential for the hepatic uptake of remnant particles after intravenous injection of chylomicron-like lipid emulsions (1). The aim of the present study was to determine the structural features of the cholesterol molecule that regulate the metabolism of chylomicrons. Chylomicron-like lipid emulsions, which reflect the size and composition and mimic the physiology of lymph chylomicrons, were prepared with tracer amounts of labeled triolein ([14C]TO) and cholesteryl oleate ([3H]CO) to follow the hydrolysis of triglyceride and the uptake of chylomicron remnant particles by the liver. Sterols selected as cholesterol congeners with functional group variations were incorporated into the emulsions in place of cholesterol and injected intravenously in rats. Control emulsions contained either no cholesterol or approximately 1% (by weight) cholesterol. The effects of the different sterol structures on lipolysis and hepatic remnant uptake were compared with controls to determine the significance of various functional groups. Clearance of emulsion CO was impaired when cholesterol was absent or replaced by cholesteryl chloride, cholesteryl formate, or 3-keto-cholesterol. Clearance of emulsions containing epicholesterol, where the OH group at the 3-position is in the alpha configuration, was similar to control emulsions containing cholesterol. Congeners with an additional hydroxyl group, viz. 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol, or 25-hydroxycholesterol, reduced CO clearance. Androstenol, which lacks the side chain at the C17-position, also retarded CO clearance from plasma. In contrast, emulsions incorporating congeners with side chain variations such as campesterol, beta-sitosterol, stigmasterol, or saturated congeners of cholesterol such as cholestanol, coprostanol and its epimer, epicoprostanol, all were cleared similarly to emulsions containing cholesterol. In conclusion, for physiological clearance of a chylomicron-like emulsion, the presence of a hydroxyl (-OH) group at the 3-position and an alkyl side chain at the C17-position of cholesterol are essential, while the structure of the side chain and the saturation of the ring structure are not critical. The mechanism of the specificity of sterols on the metabolism of protein-free emulsions is unclear, but does not relate to changes in microfluidity of the surface lipids, nor to the amount or isoform of associated apolipoproteins.
Animals↗
Measurement of expired carbon dioxide to assess the metabolism of remnant lipoproteins.
The cholesteryl esters transported from the intestine in chylomicrons are delivered to the liver. Hepatocytes take up chylomicron remnants by receptor-mediated endocytosis and the cholesteryl esters are subsequently degraded. In this study we measured the appearance in breath of labeled carbon dioxide after injection of chylomicron-like emulsions labeled with radioactive cholesteryl [1-14C]oleate. Measurements by the breath test provide an integrated assessment of capacity for clearance and subsequent metabolism of the remnants of the triglyceride-rich lipoproteins. In normal rats, mice, and rabbits injected with the radioactive emulsions, label appeared in the breath after a delay of approximately 30 min, appreciably slower than the appearance of label after injection of emulsions labeled with [14C]triolein or of [14C]oleic acid complexed with albumin. To test for the ability of the procedure to detect defects in remnant clearance, labeled emulsions were injected into diabetic rats, apoE-deficient mice, low density lipoprotein receptor (LDLr)-deficient mice, and Watanabe heritable hyperlipidemic (WHHL) rabbits with defective low density lipoprotein receptors. In rats made diabetic by treatment with streptozotocin the appearance of 14CO2 in breath was slower than in normal control rats. This finding was consistent with previous evidence from our laboratory that remnant clearance is defective in diabetic rats. In LDLr-deficient mice the appearance of 14CO2 was slower when compared with control mice and in apoE-deficient mice the appearance of 14CO2 was extremely small. In homozygous WHHL rabbits, the appearance of 14CO2 in breath was much slower than in normal control rabbits, while in heterozygous WHHL rabbits an intermediate level of appearance was found, consistent with our previous findings of defective remnant clearance in WHHL rabbits. Emulsions with cholesterol omitted, previously found to be cleared from plasma much slower than chylomicron-like emulsions, had much slower appearance of label in breath. The breath test as described is consistent with predicted metabolism of chylomicron remnants and therefore provides a useful means of assessment of remnant catabolism in the intact animal.
Animals↗
Lymphatic absorption of n - 3 polyunsaturated fatty acids from marine oils with different intramolecular fatty acid distributions.
Male Wistar rats were given 0.5 ml of either fish oil or seal oil intragastrically. The intramolecular fatty acid distributions of the triacylglycerols administered were determined by non-specific Grignard degradation followed by isolation and analysis of the 2-monoacylglycerols. The n - 3 polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (20:5(n - 3)) and docosahexaenoic acid (22:6(n - 3)), were located in outer positions (sn-1/3) in the seal oil triacylglycerols whereas the sn-2 position of fish oil triacylglycerols was enriched in 20:5(n - 3) and 22:6(n - 3). The mesenteric lymph was collected over the following 24 h and the absorption patterns of n-3 PUFAs were determined. In the lymph, the n - 3 fatty acids characteristic of the marine oils rapidly increased both with regard to mole percentage and transport (micrograms/min). There were, however, no overall significant differences in the absorption patterns over a 24 h period. The ratio between mole percentage in the oil and mole percentage in the lymph calculated at the steady-state period was significantly greater for both 20:5(n - 3) and 22:6(n - 3) following fish oil administration compared with seal oil. Initially, the recovery of n - 3 PUFAs as a percentage of the total amount transported over the experimental period was higher following injection of fish oil than seal oil but seal oil resulted in greater recovery in the last two fractions at 8 and 24 h post injection, respectively. This indicated that n - 3 PUFAs from fish oil may have been better absorbed in the initial period of digestion but overall the structure of dietary triacylglycerols had negligible effects on the assimilation of n - 3 PUFAs when these were administered as native marine oils.
Animals↗
Effects of triacylglycerol-saturated acyl chains on the clearance of chylomicron-like emulsions from the plasma of the rat.
We previously found that a single saturated acyl chain at the glycerol 2-position affected the metabolism of chylomicrons. The explanation for the effect is not clear, but could be reproduced by saturated monoacylglycerols. In the present work we have extended our measurements to several different triacylglycerols containing one or two saturated chains in specific locations in an attempt to define structural features that affect chylomicron clearance. Lipid emulsions containing triacylglycerol, egg yolk phosphatidylcholine, free cholesterol, cholesteryl oleate (CO) and labelled with 3H-CO and [14C]triolein (OOO) were prepared as models of lymph chylomicrons. When injected intravenously into rats, the metabolism of the emulsions was influenced by the acyl chains of the constituent triacylglycerols. Compared with emulsions containing OOO as the only triacylglycerol, plasma clearances of emulsion [3H]CO were extremely slow in emulsions containing either 1,2-dioleoyl-3-stearoylglycerol (OOS) or 1-stearoyl-2,3-dioleoylglycerol (SOO). As little as 10% of SOO in mixture with OOO slowed the clearance, and increasing proportions of SOO in OOO emulsions progressively slowed the removal of OOO and CO labels from plasma. With 50% and 100% SOO in the emulsions clearance was negligible. In emulsions containing the triacyl-sn-glycerols, 1,3-dimyristoyl-2-oleoylglycerol (MOM), 1,3-dipalmitoyl-2-oleoylglycerol (POP), 1-oleoyl-2,3-distearoylglycerol (OSS) or 1-palmitoyl-2-oleoyl-3-stearoylglycerol (POS), clearance rates of CO and OOO labels from plasma were significantly decreased compared with control OOO emulsions. With emulsions prepared with the triacylglycerols, 1-oleoyl-2,3-dimyristoylglycerol (OMM) and 1-oleoyl-2,3-dipalmitoylglycerol (OPP), clearances of CO label were significantly slower than with control OOO emulsions, while the removal of OOO label was not significantly affected. The uptake of CO label in the liver was decreased in conjunction with the lower rates of clearance of emulsion CO from the plasma. The clearance from plasma of 1,3-distearoyl-2-oleoylglycerol (SOS) emulsions was similar to the control OOO emulsions, but significantly more emulsion OOO label was taken up by the liver. Emulsions made with the triacylglycerols extracted from natural cocoa butter, which contained a high proportion of saturated acyl chains, were cleared similarly to the control OOO emulsions. Our findings indicate that the plasma clearance of triacylglycerol-rich lipoprotein particles depends upon the specific arrangements of the acyl chains of the constituent triacylglycerols, and not necessarily on the overall saturation of the triacylglycerols.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
The condensing effects of egg lecithin and cholesterol on triolein monolayers are inhibited by substitution of one saturated acyl chain in the triacylglycerol.
Previous work showed that the clearance from plasma of chylomicron-like emulsions injected intravenously was affected by the acyl chains of the constituent triacylglycerols. Compared with emulsions containing triolein (OOO) as the only triacylglycerol, clearances were decreased by a single saturated chain in emulsions containing 1,3-dioleoyl-2-stearoyl-sn-glycerol (OSO), 1,2-dioleoyl-3-stearoyl-sn-glycerol (OOS) or 1-stearoyl-2,3-dioleoyl-sn-glycerol (SOO). The differences in clearance may reflect physical differences at the oil-water interface related to chain interactions of the triacylglycerol structures with other lipid components. In the present work lipid monomolecular films at the air-water interface were used to establish the capacity of OOO to interact with the pure synthetic triacylglycerols OOS and SOO, and the capacity of OOS and SOO to co-exist in monolayers of lecithin and of cholesterol was compared with OOO. Substituting one oleoyl chain by a stearoyl chain induced a 20% condensation in monomolecular films of the pure triacylglycerols. Mixtures of OOO with either pure egg yolk phosphatidylcholine or cholesterol also showed substantial condensing effects. In contrast substituting one oleoyl chain by a stearoyl chain substantially lessened the condensing effects. At surface pressures above the collapse pressure of the pure triacylglycerols, substantially more OOO than OOS or SOO was retained in mixed monolayers with phosphatidylcholine. These differences could underlie the effects on metabolism of saturated chains in emulsion triacylglycerols.
Chemical Phenomena↗
Lipid and apolipoprotein B48 transport in mesenteric lymph and the effect of hyperphagia on the clearance of chylomicron-like emulsions in insulin-deficient rats.
In insulin-deficient streptozotocin-treated rats the intestine is hypertrophic and cholesterol synthesis and transport from the intestine are increased. The increased load of cholesterol is transported through the mesenteric lymph in chylomicrons. Clearance from plasma of injected chylomicrons is slowed in insulin-deficient rats, but the underlying mechanisms are currently unresolved. Hyperphagia may increase the size of chylomicrons which could contribute to defective chylomicron clearance in insulin-deficiency. In the present experiments we compared the size and number of chylomicrons in mesenteric lymph of control rats and diabetic rats infused with fat at two levels. In control and diabetic lymph-cannulated rats, as the infused dose of lipid increased the transport of triglyceride increased substantially compared with fasted rats. In contrast the transport of apoB48 increased by only a small amount during fat transport. Therefore, increased lipid transport was accomplished mostly by increased particle size, with only small increases in numbers of particles in intestinal lymph. Insulin-deficiency had no effect on triglyceride or apoB48 transport in lymph. Calculations suggested that each chylomicron particle contained a single molecule of apoB48. When hyperphagia in diabetic rats was prevented, the plasma triglycerides were decreased but the slow plasma clearance of injected chylomicron-like emulsions persisted. Hyperphagia, therefore, was unconnected to the impairment in chylomicron metabolism in insulin-deficient rats. Changes in the association with plasma apolipoproteins, in the expression of receptors for uptake of chylomicron remnants or in exposure to endothelial lipases may be responsible for the defective clearance of triacylglycerol-rich lipoproteins.
Absorption↗