Apolipoprotein E (apoE) has a high affinity to cell-surface low density lipoprotein (LDL) receptor. To determine the role of apoE in plasma lipoprotein metabolism, transgenic mouse lines with integrated rat apoE gene under the control of the metallothionein promoter were established. We found that a high expresser line produced rat apoE mainly in the liver, and the gene product was almost entirely assodated with plasma lipoproteins. The plasma level of rat apoE in homozygotes for the transgene was 17.4 mg/dl after zinc induction (vs. 4.56 mg/dl of mouse apoE in controls). In this group, plasma cholesterol and triglyceride levels were 43% and 68% reduced as compared with controls, respectively. Heterozygotes showed decreases in both lipids to a lesser extent. Gel filtration chromatography showed that lipid reduction was mainly due to decreased very low density lipoproteins (VLDL) and LDL. Especially in zinc-treated homozygotes, VLDL had almost disappeared, and a remarkable decrease in LDL and a slight decrease in high density lipoprotein were also observed. Consistently, the plasma level of apoB, a structural protein of VLDL and LDL, was 78% lower than that of controls, indicating a marked reduction in lipoproteins containing apoB. Furthermore, the transgenic mice, in contrast to controls, did not develop hypercholesterolemia when fed a high cholesterol diet. These results demonstrated that overexpression of apoE reduces plasma cholesterol and triglyceride levels and prevents diet-induced hypercholesterolemia. From dramatic and doserelated decreases in plasma lipoproteins in transgenic mice, we conclude that apoE plays a key role in plasma lipoprotein metabolism.Apolipoprotein E (apoE) is a major component ofmammalian lipoproteins along with apolipoprotein B100 (apoB100) and functions in metabolism of plasma lipoproteins through its interaction with the low density lipoprotein (LDL) receptor mainly in the liver (for a review, see ref. 1); apoE is also thought to be a specific ligand for the putative hepatic chylomicron remnant receptor (apoE receptor) (1). Expressed in many tissues, apoE plays a crucial role in transport and redistribution of lipids in peripheral tissues such as brain, peripheral nerve, and arterial wall (1). Several lines of evidence suggest that lipoproteins with several molecules of apoE have a higher affinity for LDL receptors than those without apoE (1-7). In vitro studies have shown that enrichment in apoE on very low density lipoprotein (VLDL) particles increases uptake of these lipoproteins both when cells were cultured with human VLDL that had been incubated with excess purified apoE or recombinant apoE (3,8,9) and when the transfected CHO cells overexpressing apoE were cultured with unmodified human VLDL (10). Recently, we and another group have reported that intravenous administration ofapoE causes the incorporation ofexogenous apoE onto plasma lipoproteins, enhances clearance of VLDL, and reduces the production of LDL from VLDL, resulting in a lowered plasma cholesterol l...

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Action. -Variations of the two terminal subunits of the natural products moiramide B and andrimid, the fatty acid side chain and the pyrrolidinedione group, are explored. All compounds are tested for target activity against the carboxytransferase AccAD subunits derived from S. aureus and E. coli, representing Gram-positive and Gram-negative pathogens. Antibacterial activity is measured vs. S. aureus and S. pneumoniae as Gram-positive bacteria, and vs. two E. coli strains. Variations of the fatty acid side chain show that quite diverse substituents are tolerated, cf. (VII). Despite limited influence on enzyme inhibition, a significant impact on antibacterial activity is observed. In contrast to the broad variations tolerated at the fatty acid side chain, only limited variations are tolerated in the pyrrolidinedione head group, cf. (VIII). -(POHLMANN, J.; LAMPE, T.; SHIMADA, M.; NELL, P. G.; PERNERSTORFER, J.; SVENSTRUP, N.; BRUNNER, N. A.; SCHIFFER, G.; FREIBERG*, C.; Bioorg. Med. Chem. Lett. 15 (2005) 4, 1189-1192; Dep. Anti-Infect. Res.,

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Apo E plays an important role in plasma lipoprotein metabolism through its high affinity binding to cell surface LDL receptor. In the present study, we studied the effects of apo E on the atherogenic process in Watanabe heritable hyperlipidemic rabbits which are deficient in LDL receptor and an animal model for familial hypercholesterolemia. We isolated apo E from plasma of 1% cholesterol-fed rabbits and administered 10 mg of purified apo E intravenously into five Watanabe heritable hyperlipidemic rabbits three times a week from their age of 2.5 months to 11 months for 8.5 months. After sustained administration of apo E, we found a significant reduction in the accumulation of cholesterol ester in aortae (1.55±0.07 mg/g tissue) as compared to control rabbits (4.32±0.61 mg/g tissue). Supporting this, the percentage of the surface area of the aorta with macroscopic plaque was remarkably decreased in apo Etreated animals (18.8±5.1% vs. 38.8±8.0% in control). Thus, apo E definitely prevented the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbits. (J. Clin. Invest.