triolein and Hyperlipidemias

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 14C-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 +/- 0.013 min-1, P < 0.001; cholesteryl ester: fed = 0.016 +/- 0.001; fasting = 0.040 +/- 0.006 min-1; P < 0.05) indicating that the emulsion and chylomicrons generated from the testinal lipid absorption compete 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 5-fold smaller in CAD compared to controls (0.028 +/- 0.004 and 0.141 +/- 0.069 min-1, respectively, P < 0.01). FCR of cholesteryl ester was 4-fold smaller in CAD than in controls (0.015 +/- 0.004 and 0.056 +/- 0.067 min-1 respectively, P < 0.05). These results indicate that both chylomicron lipolysis and remnant removal are diminished in CAD.

Topics: Adult; Animals; Carrier Proteins; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Chylomicrons; Coronary Disease; Dietary Fats; Disease Susceptibility; Drug Interactions; Emulsions; Female; Glycoproteins; Humans; Hyperlipidemias; Injections, Intravenous; Intestinal Absorption; Lipoproteins; Male; Middle Aged; Phosphatidylcholines; Rats; Species Specificity; Triglycerides; Triolein

Cyclosporin A (CsA) is an immunosuppressant commonly used to prevent organ rejection but is associated with hyperlipidemia and an increased risk of cardiovascular disease. Although studies suggest that CsA-induced hyperlipidemia is mediated by inhibition of low-density lipoprotein receptor (LDLr)-mediated lipoprotein clearance, the data supporting this are inconclusive. We therefore sought to investigate the role of the LDLr in CsA-induced hyperlipidemia by using Ldlr-knockout mice (Ldlr(-/-)).. Ldlr(-/-) and wild-type (wt) C57Bl/6 mice were treated with 20 mg/kg per d CsA for 4 weeks. On a chow diet, CsA caused marked dyslipidemia in Ldlr(-/-) but not in wt mice. Hyperlipidemia was characterized by a prominent increase in plasma very low-density lipoprotein and intermediate-density lipoprotein/LDL with unchanged plasma high-density lipoprotein levels, thus mimicking the dyslipidemic profile observed in humans. Analysis of specific lipid species by liquid chromatography-tandem mass spectrometry suggested a predominant effect of CsA on increased very low-density lipoprotein-IDL/LDL lipoprotein number rather than composition. Mechanistic studies indicated that CsA did not alter hepatic lipoprotein production but did inhibit plasma clearance and hepatic uptake of [(14)C]cholesteryl oleate and glycerol tri[(3)H]oleate-double-labeled very low-density lipoprotein-like particles. Further studies showed that CsA inhibited plasma lipoprotein lipase activity and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9.. We demonstrate that CsA does not cause hyperlipidemia via direct effects on the LDLr. Rather, LDLr deficiency plays an important permissive role for CsA-induced hyperlipidemia, which is associated with abnormal lipoprotein clearance, decreased lipoprotein lipase activity, and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9. Enhancing LDLr and lipoprotein lipase activity and decreasing apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9 levels may therefore provide attractive treatment targets for patients with hyperlipidemia receiving CsA.

Topics: Animals; Apolipoprotein C-III; Biomarkers; Cholesterol Esters; Cyclosporine; Disease Models, Animal; Female; Genetic Predisposition to Disease; Hyperlipidemias; Lipid Metabolism; Lipoprotein Lipase; Lipoproteins, HDL; Lipoproteins, IDL; Lipoproteins, VLDL; Liver; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Proprotein Convertase 9; Receptors, LDL; Time Factors; Triolein

Pleurotus eryngii water extract (PEE), which showed the most significant inhibitory activity against pancreatic lipase in vitro among eight edible mushrooms, was investigated to determine the mechanism of its anti-lipase activity in vitro and its hypolipidemic effect in fat-loaded mice. The inhibitory effects of mushroom extracts on pancreatic lipase activity were examined using 4-methylumbelliferyl oleate (4-MUO) or trioleoylglycerol emulsified with lecithin, gum arabic or Triton X-100 as a substrate. For in vivo experiments, blood samples were taken after oral administration of corn oil and [(3)H]trioleoylglycerol with or without PEE to food-deprived mice. PEE inhibited hydrolysis of 4-MUO and trioleoylglycerol emulsified with lecithin or Triton X-100, but not that of trioleoylglycerol emulsified with gum arabic. PEE suppressed the elevations of plasma and chylomicron triacylglycerol levels after oral administration of corn oil, but had no effect on lipoprotein lipase activity. [(3)H]Trioleoylglycerol absorption was also decreased by administration of PEE. The results of in vitro studies suggest that PEE may prevent interactions between lipid emulsions and pancreatic lipase. The hypolipidemic effect of PEE in fat-loaded mice may be due to low absorption of fat caused by the inhibition of pancreatic lipase.

Topics: Animals; Biological Products; Chylomicrons; Corn Oil; Dietary Fats; Disease Models, Animal; Emulsions; Food Deprivation; Hydrolysis; Hymecromone; Hyperlipidemias; Hypolipidemic Agents; Lipase; Lipoprotein Lipase; Male; Mice; Mice, Inbred ICR; Obesity; Phytotherapy; Plant Extracts; Pleurotus; Triglycerides; Triolein

An artificial chylomicron-like lipid emulsion doubly labeled with tri[(N)3H]oleoylglycerol ([3H]TO) and cholesteryl [1-14C]oleate ([14C]CO) was infused intravenously into human subjects with the purpose of simultaneously measuring the plasma disappearance rates (residence time, RT) of [14C]CO, which represents solely the splanchnic organ uptake of the remnant chylomicron core, and of [3H]TO, which combines the remnant disappearance with the shedding off of chylomicron triglycerides by the action of lipoprotein lipase. Thus, the fraction of the particle triglyceride content that is removed before the remnant is taken up is expressed as a delipidation index (DI = 1 - RT of [3H]TO/RT of [14C]CO. The present procedure has an advantage over the use of chylomicrons labeled with retinyl ester or radioactive triglycerides alone that represent, respectively, the chylomicron remnant or the whole particle metabolism only. When normal subjects as well as primary hyperlipidemic subjects were studied, the plasma triglyceride concentration was directly related to [14C]CO RT and [3H]TO RT, but inversely related to the delipidation index. There may be different patterns of relations between these parameters of chylomicron metabolism in primary and in secondary hyperlipidemias, as well as under the action of drugs that influence the metabolism of lipoproteins.

Topics: Adult; Aged; Cholesterol; Cholesterol Esters; Chylomicrons; Fat Emulsions, Intravenous; Female; Humans; Hypercholesterolemia; Hyperlipidemias; Lipolysis; Lipoproteins, VLDL; Male; Middle Aged; Triglycerides; Triolein

Emulsions were prepared by ultrasonication of mixtures of triolein, cholesteryl oleate, phosphatidylcholine and cholesterol in aqueous dispersions, then purified by ultracentrifugation. After injection into rats, the metabolism of the artificial, protein-free emulsions was comparable to the metabolism of chylomicrons collected from rat intestinal lymph during the absorption of fat. Like chylomicrons, the emulsion triacylglycerol was removed from the plasma more quickly than emulsion cholesteryl ester. Also like chylomicrons, much more emulsion cholesteryl ester than triacylglycerol appeared in the liver 10 min after injection, and only trace amounts appeared in the spleen. Because the artificial emulsions gained apolipoproteins when incubated with plasma, their metabolism was probably facilitated by the recipient rat plasma apolipoproteins and so, in rats made apolipoprotein-deficient by treatment with estrogen, the removal of emulsions from the plasma was slowed. Removal was also slowed in hyperlipidemic rats fed a high-fat, high-cholesterol diet to expand the plasma pools of the triacylglycerol-rich lipoproteins and remnants. The results indicate that the metabolism of lymph chylomicrons can be modeled by artificial, protein-free lipid emulsions not only in the initial partial hydrolysis by lipoprotein lipase, but also in the delivery of a remnant-like particle to the liver.

Topics: Animals; Cholesterol; Cholesterol Esters; Cholesterol, Dietary; Chylomicrons; Dietary Fats; Estrogens; Fat Emulsions, Intravenous; Hyperlipidemias; Kinetics; Liver; Microscopy, Electron; Models, Biological; Phosphatidylcholines; Rats; Triolein; Ultracentrifugation

Topics: Cholesterol; Chromatography; Chylomicrons; Cottonseed Oil; Emulsions; Esters; Fats; Fatty Acids; Female; Glycerides; Humans; Hyperlipidemias; Iodine; Iodine Isotopes; Isotope Labeling; Lipids; Lipoproteins; Lipoproteins, HDL; Male; Parenteral Nutrition; Time Factors; Triglycerides; Triolein

Topics: Adipose Tissue; Administration, Oral; Animals; Biguanides; Carbon Isotopes; Diabetes Mellitus, Experimental; Digestive System; Hyperlipidemias; Liver; Male; Rats; Rats, Inbred Strains; Triolein

Topics: Cholesterol; Chromatography, Thin Layer; Esters; Humans; Hyperlipidemias; Lipids; Methods; Spectrophotometry; Triglycerides; Triolein

Topics: Animals; Carbon Isotopes; Chromatography, Thin Layer; Ethanol; Female; Gastric Mucosa; Hyperlipidemias; Intestinal Absorption; Lipid Metabolism; Liver; Oils; Triglycerides; Triolein

Topics: Adipose Tissue; Carbon Isotopes; Chromatography, Thin Layer; Esterases; Freeze Drying; Heparin; Humans; Hydrogen-Ion Concentration; Hyperlipidemias; Kinetics; Lipids; Lipoprotein Lipase; Lipoproteins; Methods; Temperature; Triolein; Vibration

Topics: Arteriosclerosis; Blood Circulation Time; Carbohydrate Metabolism; Chylomicrons; Coronary Disease; Diabetes Mellitus; Humans; Hyperlipidemias; Hypertension; Incidence; Iodine Isotopes; Lipoprotein Lipase; Obesity; Triolein

Topics: Adenosine Triphosphate; Arteriosclerosis; Dietary Fats; Heparin; Hyperlipidemias; Hypertension; Iodine Isotopes; Niacin; Obesity; Triolein

Topics: Blood Chemical Analysis; Cholesterol; Chromatography; Chromatography, Thin Layer; Fatty Acids; Glycerides; Hyperlipidemias; Lecithins; Lipids; Palmitic Acid; Phosphatidylcholines; Phospholipids; Plasma; Research; Triolein

Topics: Biomedical Research; Blood Chemical Analysis; Chromatography; Chromatography, Paper; Colorimetry; Fats; Glycerides; Hydroxylamines; Hyperlipidemias; Lecithins; Linoleic Acid; Lipids; Palmitic Acid; Phosphatidylcholines; Research; Triolein

Topics: Arteriosclerosis; Atherosclerosis; Gastrointestinal Hormones; Glycerides; Hypercholesterolemia; Hyperlipidemias; Secretin; Triolein

Topics: Anticoagulants; Arteriosclerosis; Cholesterol; Coronary Disease; Dicumarol; Hyperlipidemias; Iodine Isotopes; Lipids; Trichloroacetic Acid; Triolein; Warfarin

Topics: Blood Chemical Analysis; Chylomicrons; Dietary Fats; Fatty Acids; Glycerides; Humans; Hypercholesterolemia; Hyperlipidemias; Lipid Metabolism; Lipids; Triolein

Topics: Celiac Disease; Cholelithiasis; Crohn Disease; Enteritis; Exocrine Pancreatic Insufficiency; Hyperlipidemias; Hyperlipoproteinemia Type I; Hyperlipoproteinemia Type III; Iodine Isotopes; Liver Diseases; Pancreatic Neoplasms; Pancreatitis; Radiometry; Sprue, Tropical; Triolein

Topics: Arteriosclerosis; Biomedical Research; Cholesterol; Diabetes Mellitus; Dietary Fats; Fatty Acids; Hyperlipidemias; Iodine Isotopes; Lipids; Triolein

Topics: Blood Chemical Analysis; Chromatography; Chromatography, Thin Layer; Glycerides; Humans; Hyperlipidemias; Infrared Rays; Lipids; Oils; Spectrophotometry, Infrared; Triolein

Topics: Arteriosclerosis; Atherosclerosis; Fats; Hyperlipidemias; Iodine Isotopes; Research; Triolein

Topics: Chromatography; Corn Oil; Heparin; Hyperlipidemias; Triolein