The Experts below are selected from a list of 234 Experts worldwide ranked by ideXlab platform
Richard J Havel - One of the best experts on this subject based on the ideXlab platform.
-
initial hepatic removal of Chylomicron remnants is unaffected but endocytosis is delayed in mice lacking the low density lipoprotein receptor
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Joachim Herz, A Oesterle, H V Desilva, Shahida Shafi, Richard J HavelAbstract:Abstract Two endocytic receptors, the low density lipoprotein (LDL) receptor (LDLR) and the LDLR-related protein (LRP), are thought to act in concert in the hepatic uptake of partially metabolized dietary lipoproteins, the Chylomicron remnants. We have evaluated the role of these two receptors in the hepatic metabolism of Chylomicron remnants in normal mice and in LDLR-deficient [LDLR (-/-)] mice. The rate of Chylomicron remnant removal by the liver was normal up to 30 min after intravenous injection of Chylomicrons into LDLR (-/-) mice and was unaffected by receptor-associated protein (RAP), a potent inhibitor of ligand binding to LRP. In contrast, endocytosis of the remnants by the hepatocytes, measured by their accumulation in the endosomal fraction and by the rate of hydrolysis of component cholesteryl esters, was dramatically reduced in the absence of the LDLR. Coadministration of RAP prevented the continuing hepatic removal of Chylomicron remnants in LDL (-/-) mice after 30 min, consistent with blockade of the slow endocytosis by a RAP-sensitive process. Taken together with previous studies, our results are consistent with a model in which the initial hepatic removal of Chylomicron remnants is primarily mediated by mechanisms that do not include LDLR or LRP, possibly involving glycosaminoglycan-bound hepatic lipase and apolipoprotein E. After the remnants bind to these alternative sites on the hepatocyte surface, endocytosis is predominantly mediated by the LDLR and also by a slower and less efficient backup process that is RAP sensitive and therefore most likely involves LRP.
-
effect of the 39 kda receptor associated protein on the hepatic uptake and endocytosis of Chylomicron remnants and low density lipoproteins in the rat
Journal of Biological Chemistry, 1994Co-Authors: Hiroshi Mokuno, Sandra Brady, Leila Kotite, Joachim Herz, Richard J HavelAbstract:Abstract The low density lipoprotein (LDL) receptor-related protein, which serves as the cell surface receptor for several proteins including alpha 2-macroglobulin-protease complexes, has been proposed to be a candidate hepatocytic receptor for Chylomicron remnants through its recognition of apolipoprotein E. We have studied the effect of two ligands for this receptor, activated alpha 2-macroglobulin and the recently described 39-kDa protein that copurifies with the LDL receptor-related protein (receptor-associated protein), on the uptake and endocytosis of Chylomicrons in intact rats and in isolated, perfused rat livers. Both of these ligands were rapidly taken up and endocytosed into the liver of rats. Chylomicrons from normal rats were injected in vivo and Chylomicrons from estradiol-treated rats that were enriched in apolipoprotein E were added to liver perfusates. Prior administration of amounts of activated alpha 2-macroglobulin that saturated hepatic uptake mechanisms did not inhibit hepatic uptake or endocytosis of endogenously labeled cholesteryl esters of Chylomicron particles in vivo or in perfused livers over a period of 15 min. By contrast, prior administration of saturating amounts of the receptor-associated protein (expressed in bacteria as a fusion protein with glutathione S-transferase) reduced hepatic uptake by about 30% and virtually abolished endocytosis. The receptor-associated protein inhibited hepatic uptake of human LDL in vivo by 70% and endocytosis by 81%. Our results show that receptor-associated protein-sensitive processes predominate in the overall pathways by which Chylomicron remnants are endocytosed by rat liver. Furthermore, they show that the receptor-associated protein binds to and inhibits the function of the LDL receptor as well as the LDL receptor-related protein.
Robert V Farese - One of the best experts on this subject based on the ideXlab platform.
-
dgat1 is not essential for intestinal triacylglycerol absorption or Chylomicron synthesis
Journal of Biological Chemistry, 2002Co-Authors: Kimberly K Buhman, Jinny S Wong, Betty J Burri, Robert L Hamilton, Nada A Abumrad, Steven J Smith, Scot J Stone, Joyce J Repa, F F Knapp, Robert V FareseAbstract:Abstract Dietary triacylglycerols are a major source of energy for animals. The absorption of dietary triacylglycerols involves their hydrolysis to free fatty acids and monoacylglycerols in the intestinal lumen, the uptake of these products into enterocytes, the resynthesis of triacylgylcerols, and the incorporation of newly synthesized triacylglycerols into nascent Chylomicrons for secretion. In enterocytes, the final step in triacylglycerol synthesis is believed to be catalyzed primarily through the actions of acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. In this study, we analyzed intestinal triacylglycerol absorption and Chylomicron synthesis and secretion in DGAT1-deficient (Dgat1 −/−) mice. Surprisingly, DGAT1 was not essential for quantitative dietary triacylglycerol absorption, even in mice fed a high fat diet, or for the synthesis of Chylomicrons. However, Dgat1 −/− mice had reduced postabsorptive Chylomicronemia (1 h after a high fat challenge) and accumulated neutral-lipid droplets in the cytoplasm of enterocytes when chronically fed a high fat diet. These results suggest a reduced rate of triacylglycerol absorption in Dgat1 −/−mice. Analysis of intestine from Dgat1 −/−mice revealed activity for two other enzymes, DGAT2 and diacylglycerol transacylase, that catalyze triacylglycerol synthesis and apparently help to compensate for the absence of DGAT1. Our findings indicate that multiple mechanisms for triacylglycerol synthesis in the intestine facilitate triacylglycerol absorption.
-
a genetic model for absent Chylomicron formation mice producing apolipoprotein b in the liver but not in the intestine
Journal of Clinical Investigation, 1995Co-Authors: Stephen G Young, Jinny S Wong, Candace M Cham, Robert E Pitas, Betty J Burri, Andrew J Connolly, Laura M Flynn, Anuradha Pappu, Robert L Hamilton, Robert V FareseAbstract:Abstract The formation of Chylomicrons by the intestine is important for the absorption of dietary fats and fat-soluble vitamins (e.g., retinol, alpha-tocopherol). Apo B plays an essential structural role in the formation of Chylomicrons in the intestine as well as the VLDL in the liver. We have developed genetically modified mice that express apo B in the liver but not in the intestine. By electron microscopy, the enterocytes of these mice lacked nascent Chylomicrons in the endoplasmic reticulum and Golgi apparatus. Because these mice could not form Chylomicrons, the intestinal villus enterocytes were massively engorged with fat, which was contained in cytosolic lipid droplets. These mice absorbed D-xylose normally, but there was virtually no absorption of retinol palmitate or cholesterol. The levels of alpha-tocopherol in the plasma were extremely low. Of note, the absence of Chylomicron synthesis in the intestine did not appear to have a significant effect on the plasma levels of the apo B-containing lipoproteins produced by the liver. The mice lacking intestinal apo B expression represent the first genetic model of defective absorption of fats and fat-soluble vitamins and provide a useful animal model for studying nutrition and lipoprotein metabolism.
Hiroshi Mokuno - One of the best experts on this subject based on the ideXlab platform.
-
effect of the 39 kda receptor associated protein on the hepatic uptake and endocytosis of Chylomicron remnants and low density lipoproteins in the rat
Journal of Biological Chemistry, 1994Co-Authors: Hiroshi Mokuno, Sandra Brady, Leila Kotite, Joachim Herz, Richard J HavelAbstract:Abstract The low density lipoprotein (LDL) receptor-related protein, which serves as the cell surface receptor for several proteins including alpha 2-macroglobulin-protease complexes, has been proposed to be a candidate hepatocytic receptor for Chylomicron remnants through its recognition of apolipoprotein E. We have studied the effect of two ligands for this receptor, activated alpha 2-macroglobulin and the recently described 39-kDa protein that copurifies with the LDL receptor-related protein (receptor-associated protein), on the uptake and endocytosis of Chylomicrons in intact rats and in isolated, perfused rat livers. Both of these ligands were rapidly taken up and endocytosed into the liver of rats. Chylomicrons from normal rats were injected in vivo and Chylomicrons from estradiol-treated rats that were enriched in apolipoprotein E were added to liver perfusates. Prior administration of amounts of activated alpha 2-macroglobulin that saturated hepatic uptake mechanisms did not inhibit hepatic uptake or endocytosis of endogenously labeled cholesteryl esters of Chylomicron particles in vivo or in perfused livers over a period of 15 min. By contrast, prior administration of saturating amounts of the receptor-associated protein (expressed in bacteria as a fusion protein with glutathione S-transferase) reduced hepatic uptake by about 30% and virtually abolished endocytosis. The receptor-associated protein inhibited hepatic uptake of human LDL in vivo by 70% and endocytosis by 81%. Our results show that receptor-associated protein-sensitive processes predominate in the overall pathways by which Chylomicron remnants are endocytosed by rat liver. Furthermore, they show that the receptor-associated protein binds to and inhibits the function of the LDL receptor as well as the LDL receptor-related protein.
Raul C. Maranhão - One of the best experts on this subject based on the ideXlab platform.
-
high cholesterol intake modifies Chylomicron metabolism in normolipidemic young men
Journal of Nutrition, 2006Co-Authors: Thais Borges Cesar, C H Mesquita, Maria Rita Marques De Oliveira, Raul C. MaranhãoAbstract:Whether the consumption of egg yolk, which has a very high cholesterol content without excess saturated fats, has deleterious effects on lipid metabolism is controversial. Absorbed dietary cholesterol enters the bloodstream as Chylomicrons, but the effects of regular consumption of large amounts of cholesterol on the metabolism of this lipoprotein have not been explored even though the accumulation of Chylomicron remnants is associated with coronary artery disease (CAD). We investigated the effects of high dietary cholesterol on Chylomicron metabolism in normolipidemic, healthy young men. The plasma kinetics of a Chylomicron-like emulsion, doubly-labeled with 14 C-cholesteryl ester ( 14 C-CIE) and 3 H-triolein ( 3 H-TG) were assessed in 25 men (17-22 y old, BMI 24.1 ± 3.4 kg/m 2 ). One group (n = 13) consumed 174 ± 41 mg cholesterol/d and no egg yolk. The other group (n = 12) consumed 3 whole eggs/d for a total cholesterol intake of 804 ± 40 mg/d. The nutritional composition of diets was the same for both groups, including total lipids and saturated fat, which comprised 25 and 7%, respectively, of energy intake. Serum LDL and HDL cholesterol and apoprotein B concentrations were higher in the group consuming the high-cholesterol diet (P < 0.05), but serum triacylglycerol, apo Al, and lipoprotein (a) did not differ between the 2 groups. The fractional clearance rate (FCR) of the 14 C-CE emulsion, obtained by compartmental analysis, was 52% slower in the high-cholesterol than in the low-cholesterol group (P < 0.001); the 3 H-TG FCR did not differ between the groups. Finally, we concluded that high cholesterol intakes increase the residence time of Chylomicron remnants, as indicated by the 14 C-CE kinetics, which may have undesirable effects related to the development of CAD.
-
delayed intravascular catabolism of Chylomicron like emulsions is an independent predictor of coronary artery disease
Atherosclerosis, 2004Co-Authors: Andrei C Sposito, Jose Antonio Franchini Ramires, Laura I Ventura, C G Vinagre, Pedro A Lemos, Edgard Quintella, Raul D Santos, Otavio Luiz Gomes Carneiro, Raul C. MaranhãoAbstract:Abstract The atherogenic role of a delayed intravascular catabolism of Chylomicrons has been suggested by univariate analysis of case-control studies. However, it is not established whether this association is caused by a direct atherogenic effect of these lipoproteins or results from the presence of concurrent and metabolically-related coronary artery disease (CAD) risk factors. In this study, the plasma kinetics of a Chylomicron-like emulsion doubly labeled with 14 C -cholesteryl oleate (CE) and 3 H -triolein (TG) was determined in 93 subjects with or without angiographically-defined CAD. As compared with controls and even after adjustment for body mass index (BMI), LDL- and HDL-cholesterol, and the presence of traditional risk factors, CAD patients had 45% smaller fractional clearance rate (FCR) of TG, 41% smaller FCR-CE and 19% smaller dilapidation index (DI; P P = 0.007), 50% smaller FCR-CE ( P = 0.01) and 27% smaller DI ( P = 0.004). In a multivariate logistic regression analysis, FCR-CE ( P P = 0.001) were the only independent predictors for the presence of CAD. In conclusion, we presently show that the rate of lipolysis and removal from the circulation of Chylomicron-like emulsions constitutes an independent predictor of CAD and a marker of CAD severity.
-
Metabolism of Chylomicrons in patients with congenital lipoatrophic diabetes: a study with emulsion models of Chylomicrons
Clinical Endocrinology, 2004Co-Authors: Bernardo Léo Wajchenberg, Rosângela F. Amâncio, Ana Tereza M. G. Santomauro, Raul C. MaranhãoAbstract:Summary background Lipoatrophic diabetes is characterized by the near absence of adipose tissue and the presence of insulin-resistant diabetes. Fasting hypertriglyceridaemia and increased postprandial lipidaemia are also present, but the metabolism of Chylomicrons, the triglyceride-rich lipoproteins in the circulation that carry the dietary fats absorbed by the intestine, was not specifically investigated. Because both the activity of insulin-dependent lipoprotein lipase that catalyses the Chylomicron lipolysis and the storage of the lipolysis products are affected in the disease, it is important to evaluate how those changes may ultimately affect the Chylomicron lipolysis and removal of Chylomicron remnants from the circulation. objective The aim of the study was to evaluate the Chylomicron intravascular metabolism in patients with lipoatrophic diabetes. patients Six patients with lipoatrophic diabetes (four females, two males) aged 22·2 ± 4·4 years, with body mass index (BMI) 21·6 ± 3·6 kg/m2, were compared with 12 healthy control subjects (seven females, five males) aged 24·3 ± 2·1 years with BMI 22·5 ± 2·7 kg/m2. measurements The plasma kinetics of intravenously injected Chylomicron-like emulsions labelled with 3H-triglycerides (3H-TG) and with 14C-cholesteryl esters (14C-CE) were determined, the former tracing the Chylomicron lipolysis by lipoprotein lipase and the latter the removal of Chylomicron remnants from the plasma. results Triglyceride values (8·3 ± 9·2 mmol/l) in the patients were higher (P
-
Chylomicron metabolism is markedly altered in systemic lupus erythematosus
Arthritis & Rheumatism, 2000Co-Authors: E F Borba, Eloisa Bonfa, Carmen G C Vinagre, Jose Antonio Franchini Ramires, Raul C. MaranhãoAbstract:Objective To verify the in vivo status of Chylomicron metabolism in systemic lupus erythematosus (SLE) since there is a high incidence of atherosclerosis in this disease and Chylomicrons may have an important role in atherogenesis. Methods A Chylomicron-like emulsion labeled with 14C-cholesteryl esters and 3H-triglycerides was injected intravenously into 10 female patients with inactive SLE and 10 healthy age- and sex-matched control subjects to determine the plasma kinetics of the emulsion lipids from consecutive plasma samples taken at regular intervals for 1 hour. Lipolytic activity was determined in vitro after incubation of the labeled emulsion with postheparin plasma. Results The decay curves for the emulsion were markedly slowed in SLE. Chylomicron lipolysis, indicated by the fractional clearance rate (FCR) of emulsion 3H-triglyceride, was 2-fold smaller in SLE patients than in controls (mean ± SD 0.023 ± 0.011 versus 0.047 ± 0.015 minute−1; P = 0.010). Chylomicron removal, indicated by emulsion 14C-cholesteryl ester FCR, was 3-fold smaller in SLE patients than in controls (0.007 ± 0.007 versus 0.023 ± 0.011 minute−1; P = 0.009). In vitro lipolysis in SLE patients was nearly half that of the controls (mean ± SD 10,199 ± 2,959 versus 6,598 ± 2,215; P = 0.014). Higher levels of very-low-density lipoprotein cholesterol and triglycerides and lower levels of high-density lipoprotein cholesterol and apolipoprotein A-I were also observed in the SLE patients. Conclusion SLE patients have disturbances in Chylomicron metabolism that are characterized by decreased lipolysis and Chylomicron remnant removal from the plasma. This finding, together with other alterations in lipid profiles that were confirmed in the present study, is largely accountable for the accelerated atherosclerotic process of the disease.
-
plasma kinetics of a Chylomicron like emulsion in patients with coronary artery disease
Atherosclerosis, 1996Co-Authors: Raul C. Maranhão, Carmen G C Vinagre, Marcia C Feres, Marcia Cristina Teixeira Martins, C H Mesquita, Odaly Toffoletto, Sergio D Gianinni, F PileggiAbstract:Chylomicron catabolism in the bloodstream consists of lipolysis by lipoprotein lipase and uptake of remnants by the liver. In rats, triglyceride-rich emulsions can mimic Chylomicron metabolism. To further validate this model in man, the emulsion was injected intravenously into fasting and into subjects previously fed a test fatty meal. The plasma kinetic curves of the emulsion 3H-triglyceride and i4C-cholesteryl ester were determined. The fractional clearance rate (FCR) of both labels was markedly reduced in the fed subjects (triglycerides: fed = 0.018 :& 0.007; fasting = 0.105 f 0.013 min-‘, P < 0.001; cholesteryl ester: fed = 0.016 k 0.001; fasting = 0.040 + 0.006 min.-‘. P < 0.05) indicating that the emulsion and Chylomicrons generated from the intestinal lipid absorption compeie for the same catabolic processes, confirming the validity of the method. The emulsion was injected into 11 patients with CAD and into 11 controls. All had plasma cholesterol < 240 and triglycerides < 250 mg/dl. FCR of triglycerides was S-fold smaller in CAD compared to controls (0.028 & 0.004 and 0.141 f 0.069 min- ‘. respectively, P < 0.01). FCR of cholesteryl ester was 4-fold smaller in CAD than in controls (0.015 f 0.004 and 0.056 i 0.067 min ~~ ’ respectively, P < 0.05). These. results indicate that both Chylomicron lipolysis and remnant removal are diminished in CAD.
Joachim Herz - One of the best experts on this subject based on the ideXlab platform.
-
initial hepatic removal of Chylomicron remnants is unaffected but endocytosis is delayed in mice lacking the low density lipoprotein receptor
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Joachim Herz, A Oesterle, H V Desilva, Shahida Shafi, Richard J HavelAbstract:Abstract Two endocytic receptors, the low density lipoprotein (LDL) receptor (LDLR) and the LDLR-related protein (LRP), are thought to act in concert in the hepatic uptake of partially metabolized dietary lipoproteins, the Chylomicron remnants. We have evaluated the role of these two receptors in the hepatic metabolism of Chylomicron remnants in normal mice and in LDLR-deficient [LDLR (-/-)] mice. The rate of Chylomicron remnant removal by the liver was normal up to 30 min after intravenous injection of Chylomicrons into LDLR (-/-) mice and was unaffected by receptor-associated protein (RAP), a potent inhibitor of ligand binding to LRP. In contrast, endocytosis of the remnants by the hepatocytes, measured by their accumulation in the endosomal fraction and by the rate of hydrolysis of component cholesteryl esters, was dramatically reduced in the absence of the LDLR. Coadministration of RAP prevented the continuing hepatic removal of Chylomicron remnants in LDL (-/-) mice after 30 min, consistent with blockade of the slow endocytosis by a RAP-sensitive process. Taken together with previous studies, our results are consistent with a model in which the initial hepatic removal of Chylomicron remnants is primarily mediated by mechanisms that do not include LDLR or LRP, possibly involving glycosaminoglycan-bound hepatic lipase and apolipoprotein E. After the remnants bind to these alternative sites on the hepatocyte surface, endocytosis is predominantly mediated by the LDLR and also by a slower and less efficient backup process that is RAP sensitive and therefore most likely involves LRP.
-
effect of the 39 kda receptor associated protein on the hepatic uptake and endocytosis of Chylomicron remnants and low density lipoproteins in the rat
Journal of Biological Chemistry, 1994Co-Authors: Hiroshi Mokuno, Sandra Brady, Leila Kotite, Joachim Herz, Richard J HavelAbstract:Abstract The low density lipoprotein (LDL) receptor-related protein, which serves as the cell surface receptor for several proteins including alpha 2-macroglobulin-protease complexes, has been proposed to be a candidate hepatocytic receptor for Chylomicron remnants through its recognition of apolipoprotein E. We have studied the effect of two ligands for this receptor, activated alpha 2-macroglobulin and the recently described 39-kDa protein that copurifies with the LDL receptor-related protein (receptor-associated protein), on the uptake and endocytosis of Chylomicrons in intact rats and in isolated, perfused rat livers. Both of these ligands were rapidly taken up and endocytosed into the liver of rats. Chylomicrons from normal rats were injected in vivo and Chylomicrons from estradiol-treated rats that were enriched in apolipoprotein E were added to liver perfusates. Prior administration of amounts of activated alpha 2-macroglobulin that saturated hepatic uptake mechanisms did not inhibit hepatic uptake or endocytosis of endogenously labeled cholesteryl esters of Chylomicron particles in vivo or in perfused livers over a period of 15 min. By contrast, prior administration of saturating amounts of the receptor-associated protein (expressed in bacteria as a fusion protein with glutathione S-transferase) reduced hepatic uptake by about 30% and virtually abolished endocytosis. The receptor-associated protein inhibited hepatic uptake of human LDL in vivo by 70% and endocytosis by 81%. Our results show that receptor-associated protein-sensitive processes predominate in the overall pathways by which Chylomicron remnants are endocytosed by rat liver. Furthermore, they show that the receptor-associated protein binds to and inhibits the function of the LDL receptor as well as the LDL receptor-related protein.