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1
Redgrave, T. G. "Chylomicron metabolism." Biochemical Society Transactions 32, no. 1 (February 1, 2004): 79–82. http://dx.doi.org/10.1042/bst0320079.
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Chylomicrons are the ‘orphans’ of the lipoprotein family. Difficulty of measurement has impeded understanding of their metabolism. Plasma concentrations of chylomicrons and chylomicron remnants give no insight into the magnitude of substrate flux through these pathways. A defect in clearance of chylomicron remnants is probably an indication of a more generalized defect in lipoprotein metabolism. Accumulating evidence supports a relationship between abnormalities in the clearance from plasma of chylomicron remnants and accelerated progression of atherosclerosis. Methods using stable isotopes in appropriately formulated emulsions are providing valuable new information.
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Phillips, Catherine, Claire Madigan, Daphne Owens, Patrick Collins, and Gerald H. Tomkin. "Defective Chylomicron Synthesis as a Cause of Delayed Particle Clearance in Diabetes?" International Journal of Experimental Diabetes Research 3, no. 3 (2002): 171–78. http://dx.doi.org/10.1080/15604280214277.
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Chylomicron metabolism is abnormal in diabetes and the chylomicron particle may play a very important role in atherosclerosis. The aim of this study was to examine the effect of diabetes on the metabolism of chylomicrons in cholesterol-fed alloxan diabetic and nondiabetic rabbits. Five diabetic rabbits and 5 control rabbits were given [C14]linoleic acid and [H3]cholesterol by gavage. Lymph was collected following cannulation of the lymph duct and radiolabelled chylomicrons were isolated by ultracentrifugation. The chylomicrons from each animal were injected into paired control and diabetic recipients. Lymph apolipoprotein (apo) B48, apo B100, and apo E were measured using sodium dodecyl sulfate–polyacrylamide gradient gel electrophoresis. Mean blood sugar of the diabetic donors and diabetic recipients were 19.7 ± 2.3 and 17.2 ± 3.2 mmol/L. Diabetic rabbits had significantly raised plasma triglyceride (10.8 ± 13.9 versus 0.8 ± 0.5 mmol/L,P< 0.02). There was a large increase in apo B48 in lymph chylomicrons in the diabetic donor animals (0.19 ± 0.10 versus 0.04 ± 0.02 mg/h,P< 0.01) and apo B100 (0.22 ± 0.15 versus 0.07 ± 0.07 mg/h,P< 0.05) and a reduction in apo E on the lymph chylomicron particle (0.27 ± 0.01 versus 0.62 ± 0.07 mg/mg apo B,P< 0.001). Diabetic recipients cleared both control and diabetic chylomicron triglyceride significantly more slowly than control recipients (P< 0.05). Clearance of control chylomicron cholesterol was delayed when injected into diabetic recipients compared to when these chylomicrons were injected into control recipients (P< 0.005). Clearance of diabetic chylomicron cholesterol was significantly slower when injected into control animals compared to control chylomicron injected into control animals (P< 0.02). In this animal model of atherosclerosis, we have demonstrated that diabetes leads to the production of an increased number of lipid and apo E–deficient chylomicron particles. Chylomicron particles from the control animals were cleared more slowly by the diabetic recipient (both triglyceride and cholesterol). The chylomicron particles obtained from the diabetic animals were cleared even more slowly when injected into the diabetic recipient. Although there was an initial delay in clearance of chylomicron triglyceride from the diabetic particle when injected into the control animals, the clearance over the first 15 minutes was not significantly different when compared to the control chylomicron injected into the control animal. On the other hand, the cholesterol clearance was significantly delayed. Thus, diabetes resulted in the production of an increased number of lipid- and apo E–deficient chylomicron particles. These alterations account, in part, for the delay in clearance of these particles.
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Tso, P., J. A. Barrowman, and D. N. Granger. "Importance of interstitial matrix hydration in intestinal chylomicron transport." American Journal of Physiology-Gastrointestinal and Liver Physiology 250, no. 4 (April 1, 1986): G497—G500. http://dx.doi.org/10.1152/ajpgi.1986.250.4.g497.
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We have shown previously that lymph flow has a profound effect on intestinal chylomicron transport. However, since lymph flow both determines the rate of convective movement of chylomicrons within the interstitium and reflects the degree of hydration of the interstitial matrix, we were unable to determine which factor was more important for the inverse relation between the chylomicron appearance time and lymph flow. In this investigation, we measured the chylomicron appearance time in rats with a normal lymph flow and expanded matrix (study A), in rats with a reduced lymph flow but expanded matrix (study B), and finally in rats with a dehydrated matrix (study C). The chylomicron appearance times were 11.7, 13.6, and 21.7 min for the rats from studies A-C, respectively. Thus, the data obtained from this study indicate that the matrix hydration may exert a more significant influence on chylomicron movement than lymph flow per se. In conclusion, the reduced chylomicron appearance time produced by expansion of the mucosal interstitium results from a diminished resistance of the interstitial matrix to chylomicron movement rather than a decreased transit time due to an enhanced convective flux of chylomicrons.
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James, AP, K. Slivkoff-Clark, and JCL Mamo. "New Insights into Cardiovascular Disease Risk in Subjects with Visceral Obesity." Asia Pacific Journal of Public Health 15, no. 1_suppl (March 2003): S37—S40. http://dx.doi.org/10.1177/101053950301500s10.
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Obese insulin resistant individuals often present with a dyslipidemic phenotype characterised by hypertriglyceridemia, low HDL cholesterol levels, essentially normal total- and LDL-cholesterol, but a propensity for smaller, denser LDL particles. We have reported that concentrations of chylomicrons are two to three folds greater than in age-matched lean controls. We have recently observed that in lean free-living subjects the flux of chylomicrons over a 12h period was just 25% greater in these subjects than basal chylomicron production. Constitutive secretion of chylomicrons appears to be of greater relevance to arterial exposure than postprandial fluctuations. Insulin critically regulates the metabolism of very low density lipoprotein (VLDL) and hence it would be expected that the hormone is also involved in the regulation of chylomicron metabolism. Impaired insulin action may therefore be responsible for the associated hyperchylomicronaemia. In this review we examine the hypothesis that insulin chronically modulates chylomicron metabolism and present evidence suggesting that hyperchylomicronaemia primarily results from impaired chylomicron production.
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Tso, P., V. Pitts, and D. N. Granger. "Role of lymph flow in intestinal chylomicron transport." American Journal of Physiology-Gastrointestinal and Liver Physiology 249, no. 1 (July 1, 1985): G21—G28. http://dx.doi.org/10.1152/ajpgi.1985.249.1.g21.
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In this study we investigated the influence of lymph flow on chylomicron transport. We examined the effects of varying the hydration of the interstitial matrix on chylomicron appearance time and on lymphatic lipid transport rate when a lipid test meal containing oleic acid and 1-monoolein was infused intraduodenally at a constant rate. The three groups of rats tested were control rats (normal interstitial hydration), rats receiving intravenous saline infusion (expanded interstitial matrix), and rats with an attenuated water absorption rate (dehydrated interstitial matrix). This study shows that lymph flow has a profound effect on intestinal chylomicron transport. As lymph flow increased, the chylomicron appearance time (time between the placement of radioactive fatty acid into the intestinal lumen to the appearance of radioactive lipid in the central lacteal) was reduced. When lymph flow exceeded 40 microliter/min, the chylomicron appearance time reached a minimum value of 13.6 min. This minimum chylomicron appearance time probably represents the time required for assembly of absorbed lipid, formation of chylomicrons, and their subsequent discharge into the lymphatics. The chylomicron appearance time lengthened as lymph flow fell. The results of this study underscore the necessity of using steady-state lymphatic lipid output data to assess factors affecting the cellular packaging and release of chylomicrons in the small intestine.
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Irawati, Deasy, John C. L. Mamo, Karin M. Slivkoff-Clark, Mario J. Soares, and Anthony P. James. "Dietary fat and physiological determinants of plasma chylomicron remnant homoeostasis in normolipidaemic subjects: insight into atherogenic risk." British Journal of Nutrition 117, no. 3 (February 14, 2017): 403–12. http://dx.doi.org/10.1017/s0007114517000150.
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AbstractTAG depleted remnants of postprandial chylomicrons are a risk factor for atherosclerosis. Recent studies have demonstrated that in the fasted state, the majority of chylomicrons are small enough for transcytosis to arterial subendothelial space and accelerate atherogenesis. However, the size distribution of chylomicrons in the absorptive state is unclear. This study explored in normolipidaemic subjects the postprandial distribution of the chylomicron marker, apoB-48, in a TAG-rich lipoprotein plasma fraction (Svedberg flotation rate (Sf>400), in partially hydrolysed remnants (Sf 20–400) and in a TAG-deplete fraction (Sf<20), following ingestion of isoenergetic meals with either palm oil (PO), rice bran or coconut oil. Results from this study show that the majority of fasting chylomicrons are within the potentially pro-atherogenic Sf<20 fraction (70–75 %). Following the ingestion of test meals, chylomicronaemia was also principally distributed within the Sf<20 fraction. However, approximately 40 % of subjects demonstrated exaggerated postprandial lipaemia specifically in response to the SFA-rich PO meal, with a transient shift to more buoyant chylomicron fractions. The latter demonstrates that heterogeneity in the magnitude and duration of hyper-remnantaemia is dependent on both the nature of the meal fatty acids ingested and possible metabolic determinants that influence chylomicron metabolism. The study findings reiterate that fasting plasma TAG is a poor indicator of atherogenic chylomicron remnant homoeostasis and emphasises the merits of considering specifically, chylomicron remnant abundance and kinetics in the context of atherogenic risk. Few studies address the latter, despite the majority of life being spent in the postprandial and absorptive state.
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Milan, Amber M., Anu Nuora, Shikha Pundir, Chantal A. Pileggi, James F. Markworth, Kaisa M. Linderborg, and David Cameron-Smith. "Older adults have an altered chylomicron response to a high-fat meal." British Journal of Nutrition 115, no. 5 (January 15, 2016): 791–99. http://dx.doi.org/10.1017/s000711451500505x.
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AbstractAgeing is associated with a prolonged and exaggerated postprandial lipaemia. This study aimed to examine the contribution of alterations in chylomicron synthesis, size and lipid composition to increased lipaemia. Healthy older (60–75 years; n 15) and younger (20–25 years; n 15) subjects consumed a high-fat breakfast. Chylomicron dynamics and fatty acid composition were analysed for 5 h in the postprandial state. Plasma TAG levels were elevated following the meal in the older subjects, relative to younger subjects (P<0·01). For older subjects compared with younger subjects, circulating chylomicron particle size was smaller (P<0·05), with greater apoB content (P<0·05) at all postprandial time points. However, total chylomicron TAG concentration between the groups was unaltered post-meal. Compared with younger subjects, the older subjects exhibited a greater proportion of oleic acid in the TAG and phospholipid (PL) fraction (P<0·05), plus lower proportions of linoleic acid in the TAG fraction of the chylomicrons (P<0·01). Thus, following the ingestion of a high-fat meal, older individuals demonstrate both smaller, more numerous chylomicrons, with a greater total MUFA and lower PUFA contents. These data suggest that the increased postprandial lipaemia of ageing cannot be attributed to increased chylomicron TAG. Rather, ageing is associated with changes in chylomicron particle size, apoB content and fatty acid composition of the chylomicron TAG and PL fractions.
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Lambert, Marc S., Kathleen M. Botham, and Peter A. Mayes. "Modification of the fatty acid composition of dietary oils and fats on incorporation into chylomicrons and chylomicron remnants." British Journal of Nutrition 76, no. 3 (September 1996): 435–45. http://dx.doi.org/10.1079/bjn19960048.
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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 infunctionally 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.
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Bowler, A., T. G. Redgrave, and J. C. L. Mamo. "Chylomicron-remnant clearance in homozygote and heterozygote Watanabe-heritable-hyperlipidaemic rabbits is defective. Lack of evidence for an independent chylomicron-remnant receptor." Biochemical Journal 276, no. 2 (June 1, 1991): 381–86. http://dx.doi.org/10.1042/bj2760381.
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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.
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Tsai, Michael Y., Angeliki Georgopoulos, James D. Otvos, Jose M. Ordovas, Naomi Q. Hanson, James M. Peacock, and Donna K. Arnett. "Comparison of Ultracentrifugation and Nuclear Magnetic Resonance Spectroscopy in the Quantification of Triglyceride-Rich Lipoproteins after an Oral Fat Load." Clinical Chemistry 50, no. 7 (July 1, 2004): 1201–4. http://dx.doi.org/10.1373/clinchem.2004.032938.
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Abstract Background: The measurement of triglyceride (TG)-rich particles after an oral fat challenge has been used to provide a measure of risk for coronary artery disease independent of the fasting plasma triglyceride concentration. The analytical “gold standard” for measuring TG-rich lipoproteins uses density gradient ultracentrifugation; however, this technique is labor-intensive. Because of our need to perform numerous postprandial analyses of TG-rich lipoproteins for a large interventional study (Genetics of Lipid Lowering Drugs and Diet Network), we evaluated the use of nuclear magnetic resonance (NMR) spectroscopy for measuring TG-rich particles. Methods: EDTA-blood samples were obtained 0, 3.5, 6, and 8 h after ingestion of an oral fat meal (89% of calories from fat) in 20 apparently healthy individuals. The plasma TG concentrations of chylomicron and chylomicron remnant/VLDL fractions were analyzed by ultracentrifugation and NMR spectroscopy. Results: Comparison of all values (n = 78) by ultracentrifugation (x) and NMR (y) produced a linear regression equation of y = 0.979x − 0.035 mmol/L (R2 = 0.90) for chylomicrons and y = 1.398x + 0.067 mmol/L (R2 = 0.96) for the fraction containing chylomicron remnants and VLDL. Postprandial response of chylomicrons and chylomicron remnant/VLDL was similar, with maximum response occurring between 3.5 to 6 h regardless of method of measurement. Conclusion: Chylomicron and chylomicron remnant/VLDL fraction measurements obtained by NMR have a high degree of correlation with results produced by ultracentrifugation. NMR may therefore be suitable as an alternative method for the measurement of postprandial TG-rich lipoproteins in individuals consuming a high-fat meal.
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Mansbach, C. M., and A. Arnold. "Steady-state kinetic analysis of triacylglycerol delivery into mesenteric lymph." American Journal of Physiology-Gastrointestinal and Liver Physiology 251, no. 2 (August 1, 1986): G263—G269. http://dx.doi.org/10.1152/ajpgi.1986.251.2.g263.
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The output of triacylglycerol in chylomicrons can be increased 60% by prefeeding rats with a 20% fat diet or 110% by including phosphatidylcholine in a lipid infusion. The present study was designed to determine whether the increment was due to an expansion of the chylomicron triacylglycerol precursor pool or an increase in its fractional turnover rate. A steady-state kinetic model was established in rats receiving 135 mumol glyceryl trioleate/h. The decay in specific activity of triacylglycerol after removal of radiolabeled glyceryl trioleate from the duodenal infusate was followed for 4 h and analyzed by the SAAM 23 program. It was found that the fractional turnover rate of the chylomicron precursor pool remained the same in each experimental condition. However, the pool was found to expand in direct proportion to the chylomicron triacylglycerol output. Functionally the infused [3H]glyceride-glycerol and tri[14C]oleate behaved the same in lymph chylomicrons and was 90% of infusate specific activity. In summary, these data suggest that increases in chylomicron triacylglycerol output are dependent on the size of the mucosal precursor pool and the monoacylglycerol acyltransferase synthetic pathway for its triacylglycerol.
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Black, Dennis D. "Development and Physiological Regulation of Intestinal Lipid Absorption. I. Development of intestinal lipid absorption: cellular events in chylomicron assembly and secretion." American Journal of Physiology-Gastrointestinal and Liver Physiology 293, no. 3 (September 2007): G519—G524. http://dx.doi.org/10.1152/ajpgi.00189.2007.
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The newborn mammal must efficiently absorb dietary fat, predominantly as triacylglycerol, and produce chylomicrons to deliver this lipid to peripheral tissues. The cellular mechanisms involved in enterocyte chylomicron assembly have recently been elucidated, and data on their regulation in the immature gut are beginning to emerge. This review focuses on key proteins involved in chylomicron assembly: apolipoprotein B-48, microsomal triglyceride transfer protein, and apolipoproten A-IV. Recent studies support a role for apolipoprotein A-IV in enhancing chylomicron secretion by promoting production of larger particles. These proteins are regulated in a manner to maximize the lipid absorptive capacity of the newborn intestine.
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Borensztajn, J., and T. J. Kotlar. "Phospholipids as modulators of hepatic recognition of chylomicron remnants. Observations with emulsified lipoprotein lipids." Biochemical Journal 269, no. 2 (July 15, 1990): 539–42. http://dx.doi.org/10.1042/bj2690539.
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The lipids extracted from chylomicrons, chylomicron remnants generated in vivo and hepatic-lipase-treated chylomicrons were emulsified by sonication. These emulsified particles retained the capacity of the native lipoproteins to be differentiated by the liver in vivo, i.e. only the particles derived from remnant and hepatic-lipase-treated chylomicron lipids were efficiently taken up by the liver. To investigate the role of phospholipids in this differentiation process, the phospholipids of all three lipoprotein preparations were separated from the remaining lipids by silicic acid chromatography. The phospholipid-free lipid fraction of chylomicrons was then emulsified with the phospholipids derived from each of the three lipoprotein preparations. Only the particles emulsified with phospholipids derived from remnants and hepatic-lipase-treated chylomicrons were efficiently taken up by the liver in vivo. These results support the proposition that phospholipids modulate the hepatic differentiation between chylomicrons and remnants in vivo.
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YU, Kenneth C. W., and John C. L. MAMO. "Chylomicron-remnant-induced foam cell formation and cytotoxicity: a possible mechanism of cell death in atherosclerosis." Clinical Science 98, no. 2 (January 11, 2000): 183–92. http://dx.doi.org/10.1042/cs0980183.
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The effects of chylomicron remnants on cytoplasmic lipid loading and cell viability were assessed in cultures of human monocyte-derived macrophages and rabbit arterial smooth muscle cells. At a cholesterol concentration of 150 μg/ml, chylomicron remnants induced substantial cytoplasmic lipid loading of macrophages, but not of smooth muscle cells, within 6 h of exposure. Chylomicron remnants were found to be cytotoxic to macrophages and smooth muscle cells, although the latter were generally more resistant. Chylomicron remnants contained no detectable oxysterols (> 1 ng) and contained less non-esterified (‘free’) fatty acids than non-lipolysed nascent chylomicrons. Chylomicron-remnant-induced cytotoxicity appeared to be time- and dose-dependent. Macrophage and smooth muscle cell viability were inversely related to the production of superoxide free radicals and were significantly improved in the combined presence of superoxide dismutase and catalase. Collectively, our data suggest that, in macrophages, cell viability is compromised as a consequence of superoxide free radical production following uptake of chylomicron remnants. We would suggest that, in arterial smooth muscle cells, chylomicron-remnant-induced cell death also occurs as a consequence of superoxide free radical production. Our observations in the present study suggest that macrophage foam cells in atherosclerotic plaques might be derived from the cellular uptake of chylomicron remnants. Furthermore, arterial accumulation of chylomicron remnants might contribute to plaque destabilization as a consequence of cell death following superoxide free radical production by macrophages and smooth muscle cells.
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Redgrave, T. G., H. L. Ly, E. C. R. Quintao, C. F. Ramberg, and R. C. Boston. "Clearance from plasma of triacylglycerol and cholesteryl ester after intravenous injection of chylomicron-like lipid emulsions in rats and man." Biochemical Journal 290, no. 3 (March 15, 1993): 843–47. http://dx.doi.org/10.1042/bj2900843.
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Chylomicrons transport fat and cholesterol via lymphatic vessels from the intestine into the bloodstream. The understanding of the metabolism of chylomicrons in man has been slowed by the difficulty of obtaining lymph chylomicrons for experimental studies. Acceptable methods for the study of chylomicron clearance in man are required, because the metabolism of chylomicrons may be abnormal in diseases such as diabetes mellitus. Metabolism of chylomicrons may also play a role in the development of atherosclerosis. In the present work, lipid emulsions were used as a physical model of chylomicrons. Triacylglycerol-rich lipid emulsions labelled with tracer amounts of radioactive triolein and cholesteryl oleate were prepared by sonication and purified by density gradient ultracentrifugation, then injected into unanaesthetized rats and normal human subjects. Plasma radioactivities were measured for 30 min in rats and 90 min in human subjects. Rat lymph chylomicrons were also injected into rats for comparison with the clearance of the lipid emulsions. The plasma clearance data for triacylglycerols and cholesteryl esters were fitted with a kinetic model using the SAAM/CONSAM programs. Multiple studies analysis of the individual studies in each group was used to obtain estimates of the parameter average values and variabilities. The plasma residence times of the lipid labels were obtained from the fitted clearance data. Our results suggest that information about chylomicron metabolism in man can be obtained by analysis of the plasma clearance data following the injection of suitably labelled chylomicron-like lipid emulsions. Our data provide a baseline for comparisons with individuals having abnormalities of lipid metabolism or risk factors for arteriosclerosis.
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Yu, Kenneth C. W., Darrin Smith, Akira Yamamoto, Akito Kawaguchi, Mariko Harada-Shiba, Taku Yamamura, and John C. L. Mamo. "Phagocytic Degradation of Chylomicron Remnants by Fibroblasts from Subjects with Homozygous Familial Hypercholesterolemia." Clinical Science 92, no. 2 (February 1, 1997): 197–203. http://dx.doi.org/10.1042/cs0920197.
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1. Familial hypercholesterolaemia is a common genetic abnormality in man characterized by premature atherogenesis as a consequence of disturbed lipoprotein metabolism. Chylomicrons, which represent intestinally derived lipoproteins, are cleared poorly in familial hypercholesterolaemia which may explain the increased retention of chylomicron remnants in arterial fatty lesions. However, cellular uptake of chylomicron remnants in familial hypercholesterolaemia remains unclear. This study determined the quantitative significance of non-low-density lipoprotein receptor-mediated uptake in fibroblasts from subjects with homozygous familial hypercholesterolaemia. 2. The metabolism of chylomicron remnants was assessed in fibroblasts from subjects with homozygous familial hypercholesterolaemia who lack low-density lipoprotein receptors. Compared with fibroblasts from normolipidaemic subjects, binding and degradation of chylomicron remnants was reduced by about two-thirds. Nevertheless, degradation of chylomicron remnants in cells from subjects with familial hypercholesterolaemia persisted in the absence of functioning low-density lipoprotein receptors. 3. Binding of chylomicron remnants to fibroblasts from subjects with familial hypercholesterolaemia was saturable. Unlabelled chylomicron remnants competed efficiently for binding but unlabelled low-density lipoprotein or a monoclonal antibody specific to the human low-density lipoprotein receptor had little effect on binding or degradation. 4. Polyinosinic acid did not alter binding and degradation of chylomicron remnants by fibroblasts from subjects with familial hypercholesterolaemia, ruling out involvement of the scavenger receptor. Lactoferrin was found to inhibit binding and degradation of chylomicron remnants by fibroblasts from subjects with familial hypercholesterolaemia by approximately 50%, implicating involvement of the α2-macroglobulin receptor. 5. Cytochalasin D blocked degradation of chylomicron remnants at 37°C in fibroblasts from subjects with familial hypercholesterolaemia by more than 80% but had no effect on binding at 4°C, consistent with a phagocytic uptake pathway. Collectively, the data suggest that chylomicron remnants bind to a cell-surface protein which initiates phagocytosis and that lactoferrin interferes with binding to this putative cell-surface protein. Phagocytic uptake of chylomicron remnants provides an additional mechanism whereby cells from subjects with familial hypercholesterolaemia can accumulate lipid.
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Sakr, Sana W., N. Attia, M. Haourigui, J. L. Paul, T. Soni, D. Vacher, and A. Girard-Globa. "Fatty acid composition of an oral load affects chylomicron size in human subjects." British Journal of Nutrition 77, no. 1 (January 1997): 19–31. http://dx.doi.org/10.1017/s0007114500002853.
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HDL-phospholipids are determinants in reverse cholesterol transport. They are mostly derived from triacylglycerol (TG)-rich lipoproteins. Chylomicron size is important, therefore, because it is related to the ratio surface phospholipids: core TG and, thus, determines the availability of postprandial phospholipids for transfer to HDL. Eleven healthy young women each ingested four different fat loads supplemented with retinyl palmitate and containing 60 g sunflower oil (SO), oleic–sunflower oil (OSO), mixed oil (MO; (g/kg) linoleic acid 480, oleic acid 380, linolenic acid 13) or beef tallow (BT). At the peak of TG absorption for all loads (4 h) chylomicron diameters, determined by agarose-gel filtration, were larger after SO compared with OSO (P< 0·05) and BT (P= 0·06) and after MO compared with BT (P< 0·05). At 6 h chylomicron size was larger after the vegetable oils compared with BT (P< 0·05 in each case). After each fat load chylomicron size decreased at 6 and 8 h compared with that at 4 h (P< 0·05) except for OSO. Retinyl ester and TG concentrations were lower in chylomicrons after BT than after the other fats but not in the chylomicron-free serum (containing chylomicron remnants), suggesting absorption in the form of very small particles. Compared with the fasting value, the concentration of the Svedberg unit of flotation 20–400 fraction, which contains VLDL and chylomicron remnants, was lower 8 h after MO, the only fat to contain significant amounts of linolenic acid. We conclude that chylomicron size is dependent on the fatty acid composition of ingested fats and the time-course of digestion, being larger for polyunsaturated fatty acid-rich fats and in the early phase of digestion. On the basis of retinyl ester concentration there were no differences between fats in chylomicron-remnant clearance.
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Tso, P., and J. A. Balint. "Formation and transport of chylomicrons by enterocytes to the lymphatics." American Journal of Physiology-Gastrointestinal and Liver Physiology 250, no. 6 (June 1, 1986): G715—G726. http://dx.doi.org/10.1152/ajpgi.1986.250.6.g715.
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Digestion of triglyceride in the intestine results in the production of 2-monoglyceride and fatty acid. Phosphatidylcholine is hydrolyzed in the lumen to form lysophosphatidylcholine before its absorption. These digestion products are absorbed by the enterocytes through simple diffusion. In contrast, cholesterol absorption seems specific and is energy dependent. After entry into the enterocytes, these lipid digestion products migrate to the endoplasmic reticulum. Both fatty acid-binding protein and sterol carrier protein may be involved in the intracellular transport of fatty acid and cholesterol, respectively. Through predominantly the monoglyceride pathway, monoglycerides and fatty acids are resynthesized to form triglyceride in the endoplasmic reticulum. The lipid droplets, coated with cholesterol, phospholipid, and apolipoproteins, are then further processed in the Golgi apparatus before being released by the enterocytes through exocytosis. As yet, little is known of the factors regulating the formation and release of these chylomicrons by the enterocytes. Although apolipoprotein B is a prerequisite for the formation of chylomicrons, the question of whether its supply is rate limiting for chylomicron formation remains to be demonstrated. Other factors that may play a role in chylomicron formation are luminal phospholipid supply, Ca2+, and microtubules. Chylomicrons and very low-density lipoproteins are probably produced by the enterocytes via different pathways. For example, Pluronic L-81, a hydrophobic surfactant, affects only chylomicron formation and has little effect on very low-density lipoprotein production. The movement of chylomicrons from the intercellular space through the basement membrane to the lamina propria is not fully understood. Once inside the lamina propria, the movement of chylomicrons is probably by diffusion and is greatly facilitated by interstitial hydration; thus the lymphogogic effect of fat absorption may serve an important function for the transfer of chylomicrons from the enterocytes to the lacteal.
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Karpe, F., T. Olivecrona, A. Hamsten, and M. Hultin. "Chylomicron/chylomicron remnant turnover in humans: evidence for margination of chylomicrons and poor conversion of larger to smaller chylomicron remnants." Journal of Lipid Research 38, no. 5 (May 1997): 949–61. http://dx.doi.org/10.1016/s0022-2275(20)37219-9.
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JUNG, Hye Rim, Scott M. TURNER, Richard A. NEESE, Steven G. YOUNG, and Marc K. HELLERSTEIN. "Metabolic adaptations to dietary fat malabsorption in chylomicron-deficient mice." Biochemical Journal 343, no. 2 (October 8, 1999): 473–78. http://dx.doi.org/10.1042/bj3430473.
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A mouse model of chylomicron deficiency was recently developed; these mice express a human apolipoprotein (apo) B transgene in the liver but do not synthesize any apoB in the intestine. Despite severe intestinal fat malabsorption, the mice maintain normal concentrations of plasma lipids and liver-derived apoB 100-containing lipoproteins. We investigated the metabolic mechanisms by which plasma lipid levels are kept normal. De novo lipogenesis (DNL) and cholesterogenesis were measured by mass isotopomer distribution analysis (MIDA). Plasma non-esterified fatty acid (NEFA) fluxes and hepatic re-esterification of labelled plasma NEFA were also measured. Hepatic and plasma triacylglycerol (TG) concentrations and plasma NEFA fluxes were not different between chylomicron-deficient mice and controls. The contribution from DNL to the hepatic TG pool was only modestly higher in chylomicron-deficient mice [12±2.1% (n = 7) compared with 3.7±1.0% (n = 9); means±S.E.M.], whereas cholesterogenesis was markedly elevated. The fractional contribution from plasma NEFA to hepatic TG was greatly elevated in the chylomicron-deficient animals (62% compared with 23%). Accordingly, 73% of hepatic TG was neither from DNL nor from plasma NEFA in controls, presumably reflecting prior contribution from chylomicron remnants, compared with only 26% in the chylomicron-deficient group. The long-term contribution from DNL to adipose fat stores reached approximately the same steady-state values (≈ 30%) in the two groups. Body fat accumulation was much lower in chylomicron-deficient animals; thus, whole-body absolute DNL was significantly lower. We conclude that plasma and hepatic TG pools and hepatic secretion of apoB-containing particles are maintained at normal levels in chylomicron-deficient mice, not by de novo fatty acid synthesis, but by more avid re-esterification of plasma NEFA, replacing the normally predominant contribution from chylomicrons, and that some dietary fat can be absorbed by apoB-independent mechanisms.
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Park, Yongsoon, Wayne J. Grellner, William S. Harris, and John M. Miles. "A new method for the study of chylomicron kinetics in vivo." American Journal of Physiology-Endocrinology and Metabolism 279, no. 6 (December 1, 2000): E1258—E1263. http://dx.doi.org/10.1152/ajpendo.2000.279.6.e1258.
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Our understanding of the metabolism of chylomicrons, the lipoprotein that transports dietary fat from the intestine to peripheral tissues, is incomplete. The present studies were conducted to determine whether a labeled intravenous lipid emulsion could be used to estimate chylomicron triglyceride (TG) rate of appearance (Ra) and thereby quantify the rate of intestinal fat absorption. After an overnight fast, healthy volunteers ( n = 6) sipped a3H-labeled drink over 6.5 h at a rate of 175 mg fat · kg−1 · h−1. Beginning at hour 5, an HPLC-purified, 14C-labeled lipid emulsion was infused intravenously for 90 min. During the study, plasma total and chylomicron TG concentrations increased from 100 ± 21 to 237 ± 40 mg/dl and from undetectable to steady-state levels of 35 ± 13 mg/dl, respectively. After a minor correction for VLDL contamination, tracer-determined chylomicron TG Ra was 175 ± 30 mg · kg−1 · h−1, equal to the presumed ingestion rate. In summary, a radiolabeled intravenous lipid emulsion is able to accurately estimate chylomicron TG Raand therefore can be used to measure in vivo fat absorption rates.
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Williams, C. M., P. A. Bateman, K. G. Jackson, and P. Yaqoob. "Dietary fatty acids and chylomicron synthesis and secretion." Biochemical Society Transactions 32, no. 1 (February 1, 2004): 55–58. http://dx.doi.org/10.1042/bst0320055.
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There is currently considerable interest in potential atherogenic and thrombogenic consequences of elevated concentrations of triacylglycerols, especially in the post-prandial state. Despite this, there is limited information on the effects of dietary fatty acids on the synthesis, secretion and metabolism of chylomicrons, the large triacylglycerol-rich lipoproteins synthesized in the enterocyte following the digestion and absorption of dietary fat. This brief review considers current approaches to the investigation of chylomicron synthesis and summarizes some of the human, cell and animal studies that have investigated effects of different fatty acids on these pathways. Potential sites for modulatory effects of dietary fatty acids on the molecular events of chylomicron synthesis are proposed in the light of the recent model that has been developed from cell and animal studies and observations based on abnormalities in chylomicron formation in human inherited autosomal recessive diseases.
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Mansbach, C. M., and R. F. Dowell. "Role of the intestine in chylomicron remnant clearance." American Journal of Physiology-Gastrointestinal and Liver Physiology 269, no. 1 (July 1, 1995): G144—G152. http://dx.doi.org/10.1152/ajpgi.1995.269.1.g144.
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When 810 mumol of [3H]glyceryl trioleate (TO) were infused intraduodenally over 6 h into rats, 29% of the triacylglycerol (TG) acyl groups in the mucosa were not from the infusate. We tested the hypothesis that chylomicron remnants contribute to the mucosal pool of nondietary TG acyl groups, since the acyl group composition of the chylomicron remnants was 58% oleate, compared with 90% in their parent chylomicrons. Purified 3H-labeled remnants were generated from chylomicrons formed in rats receiving TO intraduodenally, with 95% of the remnant disintegrations per minute (dpm) being in TG. The 3H-remnants were infused intravenously into rats receiving either saline or 135 mumol/h TO intraduodenally. In the saline-infused rats, 32% of the infused 3H dpm were in the proximal and 19% in the distal intestine and 32% were in the liver. In the fat-infused rats, 12% of the infused 3H dpm were in the proximal and 5% were in the distal gut and 29% were in the liver. When [3H]cholesterol-labeled remnants were infused intravenously and saline was infused intraduodenally, the percentage uptake into the mucosa was nearly the same as with the TG label, but comparable uptake by the liver increased. We conclude that the intestine competes with the liver for chylomicron remnant TG and cholesterol.
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Borensztajn, J., T. J. Kotlar, and S. Y. Chang. "Apoprotein-independent binding of chylomicron remnants to rat liver membranes." Biochemical Journal 279, no. 3 (November 1, 1991): 769–73. http://dx.doi.org/10.1042/bj2790769.
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Rat lymph chylomicrons and chylomicron remnants were treated with trypsin or Pronase. The ability of the resulting apoprotein-free lipoproteins to be taken up by the isolated perfused rat liver, and to bind to isolated rat liver membranes, was examined. Compared with control lipoproteins, the apoprotein-free chylomicrons and remnants retained unaltered their capacity to be differentiated by the intact liver and by the isolated membranes. Further, control remnants and apoprotein-free remnants competed for binding to the isolated membranes. We conclude that apoproteins are not required for the hepatic differentiation between chylomicrons and remnants, and suggest that the lipoprotein phospholipids may play a direct role in this process.
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Orth, Matthias, Monika Hanisch, Gerd Kröning, Mustafa Porsch-Özcürümez, Heinrich Wieland, and Claus Luley. "Fluorometric determination of total retinyl esters in triglyceride-rich lipoproteins." Clinical Chemistry 44, no. 7 (July 1, 1998): 1459–65. http://dx.doi.org/10.1093/clinchem/44.7.1459.
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Abstract A time-consuming sample preparation and measuring procedure is required for the quantitation of retinyl palmitate by HPLC. We developed a fluorometric method for the determination of total retinyl esters in chylomicrons, chylomicron remnants, and VLDL. This method is precise, sensitive, rapid, simple, and particularly useful for large-scale studies of postprandial lipid metabolism. Because the turbidity of postprandial lipemic samples interferes with the fluorescence measurement, all samples were incubated for 10 min with a clearing buffer containing esterase and detergents. This buffer eliminates the turbidity and hydrolyzes all retinyl esters to retinol. The fluorescence signal (excitation wavelength, 330 nm; emission wavelength, 490 nm) was linear from 0.1 mg/L up to 4 mg/L retinyl palmitate, and the CVs were 3.6% within-run and 5.1% within-series. A first application studied postprandial lipoproteins, which were first separated by ultracentrifugation and then subjected to size exclusion chromatography. Fluorescence analysis revealed that the chylomicron density fraction contains large amounts of chylomicron remnants.
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Hsieh, Joanne, Karin E. Trajcevski, Sarah L. Farr, Christopher L. Baker, Elizabeth J. Lake, Jennifer Taher, Jahangir Iqbal, Mahmood M. Hussain, and Khosrow Adeli. "Glucagon-Like Peptide 2 (GLP-2) Stimulates Postprandial Chylomicron Production and Postabsorptive Release of Intestinal Triglyceride Storage Pools via Induction of Nitric Oxide Signaling in Male Hamsters and Mice." Endocrinology 156, no. 10 (July 1, 2015): 3538–47. http://dx.doi.org/10.1210/en.2015-1110.
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The intestinal overproduction of apolipoprotein B48 (apoB48)-containing chylomicron particles is a common feature of diabetic dyslipidemia and contributes to cardiovascular risk in insulin resistant states. We previously reported that glucagon-like peptide-2 (GLP-2) is a key endocrine stimulator of enterocyte fat absorption and chylomicron output in the postprandial state. GLP-2's stimulatory effect on chylomicron production in the postabsorptive state has been confirmed in human studies. The mechanism by which GLP-2 regulates chylomicron production is unclear, because its receptor is not expressed on enterocytes. We provide evidence for a key role of nitric oxide (NO) in mediating the stimulatory effects of GLP-2 during the postprandial and postabsorptive periods. Intestinal chylomicron production was assessed in GLP-2-treated hamsters administered the pan-specific NO synthase (NOS) inhibitor L-NG-nitroarginine methyl ester (L-NAME), and in GLP-2-treated endothelial NOS knockout mice. L-NAME blocked GLP-2-stimulated apoB48 secretion and reduced triglycerides (TGs) in the TG-rich lipoprotein (TRL) fraction of the plasma in the postprandial state. Endothelial NOS-deficient mice were resistant to GLP-2 stimulation and secreted fewer large apoB48-particles. When TG storage pools were allowed to accumulate, L-NAME mitigated the GLP-2-mediated increase in TRL-TG, suggesting that NO is required for early mobilization and secretion of stored TG and preformed chylomicrons. Importantly, the NO donor S-nitroso-L-glutathione was able to elicit an increase in TRL-TG in vivo and stimulate chylomicron release in vitro in primary enterocytes. We describe a novel role for GLP-2-mediated NO-signaling as a critical regulator of intestinal lipid handling and a potential contributor to postprandial dyslipidemia.
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Mahley, Robert W., and M. Mahmood Hussain. "Chylomicron and chylomicron remnant catabolism." Current Opinion in Lipidology 2, no. 3 (June 1991): 170–76. http://dx.doi.org/10.1097/00041433-199106000-00005.
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Windler, E. E. T., J. Greeve, W. H. Daerr, and H. Greten. "Binding of rat chylomicrons and their remnants to the hepatic low-density-lipoprotein receptor and its role in remnant removal." Biochemical Journal 252, no. 2 (June 1, 1988): 553–61. http://dx.doi.org/10.1042/bj2520553.
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Binding and uptake of rat chylomicrons of different metabolic stages by the hepatic low-density-lipoprotein (LDL) receptor were studied. Pure chylomicrons, characterized by apolipoprotein B-48 devoid of contaminating B-100, were labelled in their cholesteryl esters. Lymph chylomicrons and serum chylomicrons, enriched in apolipoprotein E and the C-apolipoproteins, bound poorly to rat hepatic membranes. In contrast, chylomicron remnants, containing the apolipoproteins B-48 and E, bound with high affinity. Specific binding of remnants was virtually completely competed for by LDL free of apolipoprotein E. In addition, in ligand blots both remnants and LDL associated with the same protein with an Mr characteristic of the LDL receptor. Uptake of remnants during a single pass through isolated perfused rat livers was decreased to about 50% by an excess of LDL. It is concluded that rat chylomicron remnants are a ligand of the hepatic LDL receptor. The much higher affinity as compared with LDL is mediated by apolipoprotein E but not B-48, and is inhibited by the C-apolipoproteins. This explains why serum chylomicrons are not taken up by the liver, whereas remnants are rapidly removed from the circulation. Results from experiments in vivo suggest that the LDL receptor makes an important contribution to the hepatic uptake of remnants and may be the principal binding site of the liver responsible for remnant removal.
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Soued, M., and C. M. Mansbach. "Chylomicron remnant uptake by enterocytes is receptor dependent." American Journal of Physiology-Gastrointestinal and Liver Physiology 270, no. 1 (January 1, 1996): G203—G212. http://dx.doi.org/10.1152/ajpgi.1996.270.1.g203.
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During glyceryl trioleate absorption in the rat, mucosal triacylglycerol (TG) fatty acids have been shown to consist of only 71% exogenous oleate. Chylomicron remnants are enriched with endogenous TG fatty acids, compared with their parent chylomicrons, which consist primarily of exogenous TG fatty acids. Because enterocytes have the apolipoprotein B-100/E receptor, this study was directed at determining whether the cells can take up and metabolize chylomicron remnants and, if so, whether this was receptor mediated. Isolated enterocytes were incubated with purified 3H-labeled chylomicron remnants. The remnants were shown to be taken up by the basolateral membrane, not the apical membrane. Remnant uptake was proportional to time and number of enterocytes, and saturation kinetics were observed. Nonradiolabeled remnants, human low-density lipoprotein (LDL), anti-LDL receptor antibody, and receptor-associated protein, an LDL-related receptor inhibitor, were all shown to compete for or reduce 3H-remnant uptake. Remnants taken up by the enterocytes could not be removed on incubation with excess human LDL. Uptake was shown to be greatest in the villus tips of the proximal intestine. These studies suggest that enterocytes take up chylomicron remnants by a receptor-mediated process from their basolateral membranes and that the remnants could provide a source of endogenous TG fatty acids for the enterocytes.
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KENDRICK, John S., Lawrence CHAN, and Joan A. HIGGINS. "Superior role of apolipoprotein B48 over apolipoprotein B100 in chylomicron assembly and fat absorption: an investigation of apobec-1 knock-out and wild-type mice." Biochemical Journal 356, no. 3 (June 8, 2001): 821–27. http://dx.doi.org/10.1042/bj3560821.
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Editing of apolipoprotein (apo)-B100 mRNA to yield apo-B48 is a specific and developmentally regulated step in enterocytes of mammals. However, the functional significance of this step is not known. Since mice containing only apo-B100have not been documented to exhibit any difference in intestinal fat absorption from wild-type mice, the evolutionary advantage of apoB mRNA editing has been questioned. In the present study, we have compared fat absorption and chylomicron assembly in apobec-1 knock-out (KO) or wild-type (WT) mice subjected to different dietary manipulations: low-fat chow, a fat-enriched ‘Western’ diet and overnight fasting. Experiments in vivo and in vitro revealed differences in the ability of KO and WT enterocytes to assemble and secrete chylomicrons under different dietary conditions. After overnight fasting, chylomicron secretion is reduced considerably in KO compared with WT enterocytes. This is not due to reduced synthesis of apo-B or triacylglycerol (TAG), but appears to be a result of impaired assembly of chylomicrons, so that triacylglycerol accumulates in the enterocytes. After feeding with fat, secretion of chylomicrons enriched in pre-existing TAG is stimulated in KO compared with WT mice. In the present study, we have documented for the first time that apo-B100 is considerably less efficient than apo-B48 in exerting its role in the early stage of chylomicron assembly, which is rate-limiting under conditions of low dietary fat. However, this impairment is overcome by increased TAG stores that stimulate later stages in assembly, which are rate-limiting in the fat-fed state. apo-B mRNA editing may result in more efficient fat absorption, specifically under conditions of food shortage or low-fat content, and thus provide an evolutionary advantage.
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Lambert, Marc S., Michael A. Avell, Yoel Berhane, Elaine Shervill, and Kathleen M. Botham. "The differential hepatic uptake of chylomicron remnants of different fatty acid composition is not mediated by hepatic lipase." British Journal of Nutrition 85, no. 5 (May 2001): 575–82. http://dx.doi.org/10.1079/bjn2000328.
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The hypothesis that hepatic lipase mediates the differential hepatic uptake of chylomicron remnants of different fatty acid composition, demonstrated in previous work from our laboratory, was tested by investigating the effect of antibodies to the enzyme on the uptake of remnants enriched with saturated or n-3 polyunsaturated fatty acids by the perfused rat liver. After perfusion of rat livers with polyclonal antibodies to rat hepatic lipase raised in rabbits or with rabbit non-immune serum for 15 min, [3H]oleate-labelled chylomicron remnants, derived from chylomicrons of rats given a bolus of either palm (rich in saturated fatty acids) oil or fish (rich in n-3 polyunsaturated fatty acids) oil, were added. The disappearance of radioactivity from the perfusate during 120 min and its recovery in the liver at the end of the experiments were then measured. Although the rabbit anti-rat hepatic lipase antiserum was shown to inhibit hepatic lipase activity by up to 90 %, and to bind extensively to hepatic sinusoidal surfaces when added to the perfusate, radioactivity from remnants of chylomicrons from rats given a bolus of fish oil as compared with palm oil disappeared from the perfusate and appeared in the liver more rapidly in the presence both the antiserum and the non-immune serum, and the differences between the uptake of the two types of remnants were similar. We conclude, therefore, that differential interaction with hepatic lipase is not responsible for the differences in the rate of removal of chylomicron remnants of different fatty acid composition from the blood.
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Mardy, Kai, Darrell D. Belke, and David L. Severson. "Chylomicron metabolism by the isolated perfused mouse heart." American Journal of Physiology-Endocrinology and Metabolism 281, no. 2 (August 1, 2001): E357—E364. http://dx.doi.org/10.1152/ajpendo.2001.281.2.e357.
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The catabolism of rat chylomicrons, labeled in their triacylglycerol (TG) component, was investigated using perfused working mouse hearts. Perfusion of mouse hearts with heparin increased lipoprotein lipase (LPL) activity in the perfusate. This heparin-releasable LPL pool remained constant over a variety of experimental conditions, including workload and fatty acid concentrations, making the mouse heart a suitable model to study chylomicron catabolism. Endothelium-bound LPL hydrolyzed radiolabeled 3H-labeled chylomicrons (0.4 mM TG); the fate of LPL-derived 3H-labeled fatty acids was split evenly between oxidation (production of3H2O) and esterification (incorporation into tissue lipids, mainly TG). In comparison, the oxidation of 0.4 mM [3H]palmitate complexed to albumin was fourfold greater than esterification into tissue lipids. Surprisingly, the addition of unlabeled palmitate (0.4 or 1.2 mM) to perfusions with3H-chylomicrons did not affect the fate (either oxidation or esterification) of LPL-derived 3H-fatty acids. These results suggest that fatty acids produced from lipoprotein hydrolysis by the action of LPL and fatty acids from a fatty acid-albumin complex do not enter a common metabolic pool in the heart.
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Mansbach, Charles M., and Shahzad Siddiqi. "Control of chylomicron export from the intestine." American Journal of Physiology-Gastrointestinal and Liver Physiology 310, no. 9 (May 1, 2016): G659—G668. http://dx.doi.org/10.1152/ajpgi.00228.2015.
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The control of chylomicron output by the intestine is a complex process whose outlines have only recently come into focus. In this review we will cover aspects of chylomicron formation and prechylomicron vesicle generation that elucidate potential control points. Substrate (dietary fatty acids and monoacylglycerols) availability is directly related to the output rate of chylomicrons. These substrates must be converted to triacylglycerol before packaging in prechylomicrons by a series of endoplasmic reticulum (ER)-localized acylating enzymes that rapidly convert fatty acids and monoacylglycerols to triacylglycerol. The packaging of the prechylomicron with triacylglycerol is controlled by the microsomal triglyceride transport protein, another potential limiting step. The prechylomicrons, once loaded with triacylglycerol, are ready to be incorporated into the prechylomicron transport vesicle that transports the prechylomicron from the ER to the Golgi. Control of this exit step from the ER, the rate-limiting step in the transcellular movement of the triacylglycerol, is a multistep process involving the activation of PKCζ, the phosphorylation of Sar1b, releasing the liver fatty acid binding protein from a heteroquatromeric complex, which enables it to bind to the ER and organize the prechylomicron transport vesicle budding complex. We propose that control of PKCζ activation is the major physiological regulator of chylomicron output.
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CHANG, Suyi, Nobuyo MAEDA, and Jayme BORENSZTAJN. "The role of lipoprotein lipase and apoprotein E in the recognition of chylomicrons and chylomicron remnants by cultured isolated mouse hepatocytes." Biochemical Journal 318, no. 1 (August 15, 1996): 29–34. http://dx.doi.org/10.1042/bj3180029.
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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 °C LPL did not enhance the binding of the normal or apo E-free chylomicrons by the hepatocytes. When incubations were performed at 37 °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.
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Lo, Chun-Min, Brian K. Nordskog, Andromeda M. Nauli, Shuqin Zheng, Sarah B. vonLehmden, Qing Yang, Dana Lee, Larry L. Swift, Nicholas O. Davidson, and Patrick Tso. "Why does the gut choose apolipoprotein B48 but not B100 for chylomicron formation?" American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 1 (January 2008): G344—G352. http://dx.doi.org/10.1152/ajpgi.00123.2007.
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Chylomicrons produced by the human gut contain apolipoprotein (apo) B48, whereas very-low-density lipoproteins made by the liver contain apo B100. To study how these molecules function during lipid absorption, we examined the process as it occurs in apobec-1 knockout mice (able to produce only apo B100; KO) and in wild-type mice (of which the normally functioning intestine makes apo B48, WT). Using the lymph fistula model, we studied the process of lipid absorption when animals were intraduodenally infused with a lipid emulsion (4 or 6 μmol/h of triolein). KO mice transported triacylglycerol (TG) as efficiently as WT mice when infused with the lower lipid dose; when infused with 6 μmol/h of triolein, however, KO mice transported significantly less TG to lymph than WT mice, leading to the accumulation of mucosal TG. Interestingly, the size of lipoprotein particles from both KO and WT mice were enlarged to chylomicron-size particles during absorption of the higher dose. These increased-size particles produced by KO mice were not associated with increased apo AIV secretion. However, we found that the gut of the KO mice secreted fewer apo B molecules to lymph (compared with WT), during both fasting and lipid infusion, leading us to conclude that the KO gut produced fewer numbers of TG-rich lipoproteins (including chylomicron) than the wild-type animals. The reduced apo B secretion in KO mice was not related to reduced microsomal triglyceride transfer protein lipid transfer activity. We propose that apo B48 is the preferred protein for the gut to coat chylomicrons to ensure efficient chylomicron formation and lipid absorption.
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van Dijk, M. C. M., G. J. Ziere, W. Boers, C. Linthorst, M. K. Bijsterbosch, and T. J. C. van Berkel. "Recognition of chylomicron remnants and β-migrating very-low-density lipoproteins by the remnant receptor of parenchymal liver cells is distinct from the liver α2-macroglobulin-recognition site." Biochemical Journal 279, no. 3 (November 1, 1991): 863–70. http://dx.doi.org/10.1042/bj2790863.
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The uptake in vivo of chylomicrons and beta-migrating very-low-density lipoprotein (beta-VLDL) by rat liver, which is primarily carried out by parenchymal cells, is inhibited, 5 min after injection, to respectively 35 and 8% of the control values after preinjection of lactoferrin. The decrease in the uptake of lipoproteins by the liver caused by lactoferrin is a specific inhibition of uptake by parenchymal cells. Competition studies in vitro demonstrate that chylomicron remnants and beta-VLDL compete for the same recognition site on parenchymal cells. Data obtained in vivo together with the competition studies performed in vitro indicate that chylomicron remnants and beta-VLDL interact specifically with the same remnant receptor. Hepatic uptake of 125I-labelled-alpha 2-macroglobulin in vivo, mediated equally by parenchymal and endothelial cells, is not decreased by preinjection of lactoferrin and no effect on the parenchymal-cell-mediated uptake is found. In vitro, alpha 2-macroglobulin and chylomicron remnants or beta-VLDL show no cross-competition. Culturing of parenchymal cells for 24-48 h leads to a decrease in the cell association of alpha 2-macroglobulin to 26% of the initial value, while the cell association of beta-VLDL with the remnant receptor is not influenced. It is concluded that beta-VLDL and chylomicron remnants are recognized by a specific remnant receptor on parenchymal liver cells, while uptake of alpha 2-macroglobulin by liver is carried out by a specific receptor system (presumably involving the LDL-receptor-related protein) which shows properties that are distinct from those of the remnant receptor.
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Orth, Matthias, Claus Luley, and Heinrich Wieland. "Effects of VLDL, chylomicrons, and chylomicron remnants on platelet aggregability." Thrombosis Research 79, no. 3 (August 1995): 297–305. http://dx.doi.org/10.1016/0049-3848(95)00116-9.
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Bernik, Márcia MS, Joel C. Heimann, Edna R. Nakandakare, Patrícia M. Cazita, Valéria S. Nunes, Jussara C. Rocha, Mônica QTS Neves, and Eder CR Quintão. "Effects of hydrochlorothiazide and propranolol treatment on chylomicron metabolism in hypertensive subjects." Canadian Journal of Physiology and Pharmacology 83, no. 7 (July 1, 2005): 617–23. http://dx.doi.org/10.1139/y05-051.
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Modifications in chylomicron metabolism caused by antihypertensive drugs were investigated in hypertensive subjects because previous studies had indicated that diuretics and beta-blockers modify the plasma lipid concentrations through mechanisms that were not fully understood. A triglyceride-rich emulsion resembling lymph chylomicrons, labeled with (3H) triolein and (14C) cholesteryl oleate, was infused intravenously into mildly hypertensive patients after 8 weeks on placebo and subsequently on hydrochlorothiazide (n = 10) or propranolol (n = 8). The residence time of both radioactivities in plasma was utilized for the simultaneous calculation of the particle remnant removal rate and of the lipoprotein lipase activity expressed as a delipidation index = 1 [(3H) triolein residence time/(14C) cholesteryl oleate residence time]. Treatment with hydrochlorothiazide diminished the delipidation rate value whereas propranolol mildly increased the removal rate of the remnant particle. These alterations of the chylomicron kinetics were not accompanied by changes in plasma triglycerides, glucose, and insulin concentration as measured in the fasting state. The impairment of the lipoprotein lipase activity by thiazides and the faster removal rate of the whole particle by propranolol could explain the reason why in previous clinical studies the simultaneous use of these drugs does not aggravate the hyperlipidemia known to be induced by thiazides alone. Key words: hydrochlorothiazide, propranolol, hypertension, plasma lipoproteins, chylomicron metabolism.
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Hussain, M. M., R. W. Mahley, J. K. Boyles, P. A. Lindquist, W. J. Brecht, and T. L. Innerarity. "Chylomicron metabolism." Journal of Biological Chemistry 264, no. 30 (October 1989): 17931–38. http://dx.doi.org/10.1016/s0021-9258(19)84662-8.
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Beisiegel, U., and J. Heeren. "Chylomicron pathways." Atherosclerosis 144 (May 1999): 3. http://dx.doi.org/10.1016/s0021-9150(99)80003-3.
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Williams, Christine M. "Dietary interventions affecting chylomicron and chylomicron remnant clearance." Atherosclerosis 141 (December 1998): S87—S92. http://dx.doi.org/10.1016/s0021-9150(98)00224-x.
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de Bari, Ornella, Brent A. Neuschwander-Tetri, Min Liu, Piero Portincasa, and David Q. H. Wang. "Ezetimibe: Its Novel Effects on the Prevention and the Treatment of Cholesterol Gallstones and Nonalcoholic Fatty Liver Disease." Journal of Lipids 2012 (2012): 1–16. http://dx.doi.org/10.1155/2012/302847.
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The cholesterol absorption inhibitor ezetimibe can significantly reduce plasma cholesterol concentrations by inhibiting the Niemann-Pick C1-like 1 protein (NPC1L1), an intestinal sterol influx transporter that can actively facilitate the uptake of cholesterol for intestinal absorption. Unexpectedly, ezetimibe treatment also induces a complete resistance to cholesterol gallstone formation and nonalcoholic fatty liver disease (NAFLD) in addition to preventing hypercholesterolemia in mice on a Western diet. Because chylomicrons are the vehicles with which the enterocytes transport cholesterol and fatty acids into the body, ezetimibe could prevent these two most prevalent hepatobiliary diseases possibly through the regulation of chylomicron-derived cholesterol and fatty acid metabolism in the liver. It is highly likely that there is an intestinal and hepatic cross-talk through the chylomicron pathway. Therefore, understanding the molecular mechanisms whereby cholesterol and fatty acids are absorbed from the intestine could offer an efficacious novel approach to the prevention and the treatment of cholesterol gallstones and NAFLD.
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Borensztajn, J., T. J. Kotlar, and C. A. Matza. "Heparin-binding apoproteins. Effects on lipoprotein lipase and hepatic uptake of remnants." Biochemical Journal 233, no. 3 (February 1, 1986): 909–12. http://dx.doi.org/10.1042/bj2330909.
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Apoprotein-free heparin-binding and non-binding chylomicrons were used as substrates to test the effects on lipoprotein lipase activity of (a) chylomicron protein I; (b) the mixture of proteins I, II and apoprotein E and (c) human beta 2-glycoprotein I. No activation of the enzyme was observed with any of those apoproteins. When rats were injected simultaneously with [3H]cholesterol-labelled heparin-binding chylomicrons (containing proteins I and II) and [14C]cholesterol-labelled non-binding chylomicrons, no differences were detected between the rates of removal from circulation of those two types of particles. Clearance of chylomicrons from circulation was accompanied by the incorporation of 3H and 14C labels into the livers at similar rates. It is concluded that proteins I, II and apoprotein E have no effect on the degradation of chylomicrons by lipoprotein lipase and that the hepatic recognition of remnants does not appear to be affected by proteins I and II.
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Felts, James M. "The quantitative separation of chylomicrons and chylomicron remnants by column chromatography." Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 918, no. 1 (March 1987): 93–96. http://dx.doi.org/10.1016/0005-2760(87)90013-0.
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Levy, Emile. "The 1991 Borden Award Lecture. Selected aspects of intraluminal and intracellular phases of intestinal fat absorption." Canadian Journal of Physiology and Pharmacology 70, no. 4 (April 1, 1992): 413–19. http://dx.doi.org/10.1139/y92-052.
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The recognition of chylomicrons as dietary lipid transporters dates back to more than 70 years and marks a milestone in lipoprotein history. Conventionally, three phases constitute the process of absorption of exogenous fat: intraluminal, intestinal, and delivery. The intraluminal phase includes chemical hydrolysis by lipolytic enzymes and the micellar solubilization of lipolytic products by bile acids. The intestinal phase comprises the diffusion of micelles through the unstirred water layer, passive diffusion across the microvillous membrane of the enterocyte, and the formation of lipid-carrying lipoproteins. The delivery phase involves the exocytosis of chylomicrons from the absorptive cells and their subsequent removal by lymphatic structures and the systemic circulation. The precise steps and factors involved in all phases of chylomicron synthesis are not yet known, but both experimental and clinical studies have been helpful. Of the inborn metabolic disorders, the prerequisite function of apolipoprotein (apo B) for the assembly and release of lipoprotein particles stood out. Moreover, evidence emerged that the enterocyte produces apo B-100 in addition to apo B-48. Calcium and essential fatty acid status originates as determinants for triglyceride-rich particle synthesis. Furthermore, the developmental changes and regulatory factors of lipoprotein elaboration represent excellent tools in the study of the intracellular mechanisms of lipid transport.Key words: intestinal fat absorption, chylomicron, lipoproteins and apoproteins, ontogeny, essential fatty acid deficiency, calcium.
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Karpe, F., A. S. Bickerton, L. Hodson, B. A. Fielding, G. D. Tan, and K. N. Frayn. "Removal of triacylglycerols from chylomicrons and VLDL by capillary beds: the basis of lipoprotein remnant formation." Biochemical Society Transactions 35, no. 3 (May 22, 2007): 472–76. http://dx.doi.org/10.1042/bst0350472.
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The triacylglycerol content of chylomicrons and VLDL (very-low-density lipoprotein) compete for the same lipolytic pathway in the capillary beds. Although chylomicron triacylglycerols appear to be the favoured substrate for lipoprotein lipase, VLDL particles compete in numbers. Methods to quantify the specific triacylglycerol removal from VLDL and chylomicrons may involve endogenous labelling of the triacylglycerol substrate with stable isotopes in combination with arteriovenous blood sampling in humans. Arteriovenous quantification of remnant lipoproteins suggests that adipose tissue with its high lipoprotein lipase activity is a principal site for generation of remnant lipoproteins. Under circumstances of reduced efficiency in the removal of triacylglycerols from lipoproteins, there is accumulation of remnant lipoproteins, which are potentially atherogenic.
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Wathne, K. O., B. Carlander, K. R. Norum, and R. Blomhoff. "Uptake of retinyl ester in HL-60 cells via the low-density-lipoprotein-receptor pathway." Biochemical Journal 257, no. 1 (January 1, 1989): 239–44. http://dx.doi.org/10.1042/bj2570239.
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Newly absorbed retinol is transported in association with chylomicrons and their remnants. In addition, after intake of high doses of retinol, significant amounts are also found in low-density lipoprotein (LDL). As both chylomicron remnants and LDL may be taken up by cells via the LDL receptor, and retinoids inhibit proliferation of some leukaemic cells, we have studied the uptake of retinol in leukaemic cells via the LDL-receptor pathway. HL-60 cells contain saturable binding sites for LDL. The binding of LDL to its receptor has a dissociation constant of about 3.2 x 10(-9) M, and the number of receptors per cell was calculated to be about 2700. Uptake of 125I-LDL by HL-60 cells was increased 2-fold by preincubating the cells with mevinolin. The presence of specific receptors for LDL on HL-60 cells was further confirmed by the finding that exogenous LDL cholesterol was able to up-regulate the ACAT (acyl-CoA: cholesterol acyltransferase) activity of HL-60 cells. We then tested the uptake of retinyl ester in leukaemic cells via the LDL-receptor pathway. HL-60 cells were incubated with LDL or chylomicron remnants labelled with [3H]retinyl palmitate. Uptake of retinyl ester associated with both LDL and chylomicron remnants was observed. Furthermore, the presence of excess LDL decreased the uptake by 75-100%, supporting the hypothesis that the uptake of retinyl ester occurred via the LDL receptor in HL-60 cells.
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ELSEGOOD, Caryn L., Sebely PAL, Paul D. ROACH, and John C. L. MAMO. "Binding and uptake of chylomicron remnants by primary and THP-1 human monocyte-derived macrophages: determination of binding proteins." Clinical Science 101, no. 2 (June 18, 2001): 111–19. http://dx.doi.org/10.1042/cs1010111.
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The binding and uptake of chylomicron remnants by human macrophages was studied in order to resolve paradoxical observations that have described the putative mechanisms by which postprandial lipoproteins induce foam cell formation. Chylomicron remnants bound to human monocyte-derived macrophages (HMMs) and to the transformed monocytic cell line THP-1 with high affinity (Kd of approx. 5.5 µg of chylomicron remnant protein/ml). Binding was found to be saturable for both cell types, and was strongly inhibited in the presence of unlabelled chylomicron remnants. Ligand blot studies with colloidal-gold-labelled chylomicron remnants identified two cell surface binding sites on both HMMs and THP-1 cells, with molecular masses of approx. 128 kDa and 43 kDa. The high-molecular-mass binding site was found to be the low-density lipoprotein (LDL) receptor, based on the strong inhibition of chylomicron remnant binding in the presence of unlabelled LDL, Fab2 antibody fragments to the LDL receptor or calcium chelators. Competition studies suggested that, in HMMs, the LDL receptor appeared to facilitate approximately half of the total chylomicron remnant uptake. In contrast, the LDL receptor was not significantly involved in macrophage uptake of chylomicron remnants by THP-1 cells. The identity of the 43 kDa binding site is presently unknown, but, importantly, expression was not inhibited as a consequence of sterol loading, which was induced by incubating HMMs and THP-1 cells with 25-hydroxycholesterol. In contrast, the expression of the LDL receptor was substantially attenuated following lipid loading. Collectively, our data suggest that, while the macrophage LDL receptor can bind chylomicron remnants and facilitate uptake in non-lipid-loaded HMMs, other sterol-insensitive sites are responsible for the unabated uptake of chylomicron remnants by macrophages. We propose that the 43 kDa macrophage chylomicron remnant binding protein may be a candidate for the sterol loading of macrophages.
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Nauli, Andromeda M., Shuqin Zheng, Qing Yang, Ronggui Li, Ronald Jandacek, and Patrick Tso. "Intestinal alkaline phosphatase release is not associated with chylomicron formation." American Journal of Physiology-Gastrointestinal and Liver Physiology 284, no. 4 (April 1, 2003): G583—G587. http://dx.doi.org/10.1152/ajpgi.00482.2002.
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Intestinal alkaline phosphatase (IAP) is one of the major sources of alkaline phosphatase in circulation. It is secreted into the intestinal lumen, serum, and lymph. After the ingestion of lipid, lymphatic alkaline phosphatase secretion increases significantly. We have found that the nonabsorbable fat olestra is unable to stimulate lymphatic alkaline phosphatase secretion. We also found that the hydrophobic surfactant Pluronic L-81, which blocks chylomicron formation, fails to inhibit this increase in lymphatic alkaline phosphatase secretion. These results suggest that it is the lipid uptake into the mucosa and/or reesterification to form triacylglycerols, but not the formation of chylomicrons, that is necessary for the stimulation of the secretion of alkaline phosphatase into the lymph.
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Desaldeleer, Cécile, Sebastien Henno, Bertrand Bruneau, and Alain Dabadie. "Chylomicron retention disease." Digestive and Liver Disease 45, no. 2 (February 2013): e3. http://dx.doi.org/10.1016/j.dld.2012.08.003.
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