The metabolism of chylomicron remnants in mice deficient in low density lipoprotein receptor (LDLr) or apolipoprotein E (apoE) was compared with that of control C57BL/6J mice. Mice were injected intravenously with chylomicron-like emulsions labeled with radioactive lipids. Blood samples were taken at fixed time intervals from the retro-orbital sinus, and clearance rates of the lipoproteins were assessed from the decline in plasma radioactivities. To follow the intracellular pathway of remnants in the liver, emulsions labeled with a fluorescent cholesteryl ester (BODIPY) were injected, and liver sections were processed and assayed by laser confocal microscopy. Catabolism of remnant cholesteryl esters was assessed by injecting emulsions labeled with cholesteryl[1-14 C]oleate and measuring the expired CO 2 from each animal.In apoE-deficient mice, remnant removal from plasma was totally impeded, while the clearance of remnants in LDLr-deficient mice was similar to that in C57BL/6J control mice. The confocal micrographs of livers 20 min after injection of fluorescent chylomicron-like emulsions showed evenly distributed fluorescent particles in the hepatocytes from control mice. In contrast, the fluorescent particles were mainly located in sinusoidal spaces in LDLr-deficient mice. Three hours after injection the livers from control mice showed few fluorescent particles, indicating that remnants have been catabolized, while the sections from LDLr-deficient mice were still highly fluorescent. Micrographs from apoE-deficient mice showed no fluorescent particles in the liver at any time after injection. Measurement of expired radioactive CO 2 after injection of emulsions labeled in the fatty acid moiety of cholesteryl oleate indicated that remnant metabolism was slower in the LDLr-deficient mice and essentially nil in the apoE-deficient mice. Control mice had expired 50% of the injected label by 3 h after injection.We conclude that under normal circumstances, chylomicron remnants are rapidly internalized by LDLr and catabolized in hepatocytes, with a critical requirement for apoE. When LDLr is absent, remnants are taken up by a second apoE-dependent pathway, first to the sinusoidal space of the liver, with subsequent slow endocytosis and slow catabolism. Hepatic clearance via this second pathway is increased by heparin, inhibited by lactoferrin, heparinase, and suramin, and down-regulated by feeding a high fat diet.Chylomicrons are responsible for transporting most dietary lipids from the intestinal tract into the bloodstream. Along with the bulk of lipids in the form of triacylglycerols (triglycerides) and phospholipids, a small proportion of the total mass of chylomicron is made up of cholesterol and cholesteryl esters. In the circulation, chylomicrons are metabolized by a two-stage process. Initially, the majority of the triglyceride is hydrolyzed by the action of lipoprotein lipase and taken up by extrahepatic tissues. The resulting smaller particles, known as chylomicron remnants, contain the residual triglyceride an...

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The metabolism of oxidized chylomicrons (ox-CMs) was investigated in vivo. CMs from rats fed corn, linseed, or fish oil were oxidized by incubation with 2,2'-azobis(2-amidinopropane)hydrochloride (AAPH) or sodium hypochlorite (NaOCl). Oxidized CMs had a rapid phase of clearance, followed by a slow phase. Clearance of ox-CMs was decreased for corn oil but increased for linseed and fish oil particles. Differences in rats of uptake between CM types or treatment were independent of the rate of remnant formation, but were instead a consequence of decreased clearance. A greater triglyceride-to-cholesteryl ester ratio in liver suggested that there was less lipolysis of ox-CM triglyceride prior to uptake. Hepatic uptake of ox-CMs was decreased, whereas there was increased uptake in spleen. However, the uptake by Kupffer cells of ox-CMs was 43% of total liver uptake after AAPH treatment and 59% after NaOCl treatment, compared with 21% for control CMs. Collectively, our data show that oxidation can have differential effects on the rate of clearance of CMs and that ox-CMs are preferentially cleared by the reticuloendothelial system.

In previous work we found that sterols such as cholesterol were essential for physiological plasma clearance of lipid emulsions mimicking the structure of mammalian triglyceride-rich lipoproteins. In the present study we compared the clearances of emulsions prepared with sterols of varying alkyl chain length (straight chains, n -C3 to n -C7, or branched chains, i -C5 to i -C10) at the C-17 position. Our studies show that the length of the alkyl chain at the C-17 position of sterols markedly affects the removal of remnant particles from the plasma of rats traced by emulsion cholesteryl oleate label. An alkyl chain of 7 carbons or more was needed for normal remnant clearance. Straight and branched chains of similar length were cleared similarly, showing that the presence of a branch at the end of the alkyl chain had no effect on remnant clearance. For side chains of 7 carbons or less, substitution of sterols with an unsaturation in the alkyl chain close to the terminal carbon markedly decreased the clearance of remnants. Triolein label was used to estimate lipolysis of the injected emulsions. Lipolysis was little affected by the structure of the sterol side chain, except that lipolysis was markedly higher with emulsions containing sterols with an alkyl chain having 4 carbon atoms ( n -C4) or with an unsaturation in the 4 carbon alkyl chain.We conclude that the length of the alkyl side chain is an important element in the essentiality of cholesterol as a regulator of metabolism of lipid emulsion models of triglyceride-rich lipoproteins.-Martins, I. J., C. Vilchèze, B-C. Mortimer, R. Bittman, and T. G. Redgrave. Sterol side chain length and structure affect the clearance of chylomicron-like lipid emulsions in rats and mice.