Ability of the LDL receptor from several animal species to recognize the human apo B binding domain: studies with LDL from familial defective apo B-100

Corsini, Alberto; Mazzotti, Matteo; Villa, Alexander; Maggi, F.M.; Bernini, Franco; Romanò, Luca; Romano, C.; Fumagalli, R.; Catapano, A.L.

doi:10.1016/0021-9150(92)90203-s

Cited by 30 publications

(12 citation statements)

References 32 publications

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“…Maeda and coworkers (42) showed that both human and mouse apoE bind to mouse LDL receptors with similar affinity and binding maximum, whereas human apoE is cleared poorly by LDL receptor-independent mechanisms in the mouse. In contrast, human apoB (LDL) binds to mouse LDL receptors with lower affinity than that of mouse apoB (43), and the hepatic clearance rate of human LDL in the mouse is 2.4-fold slower than that of mouse LDL (44). Thus, although our clearance data for the apoB component of the total lipoprotein fraction (see supplementary Fig.…”

Section: Discussionmentioning

confidence: 83%

Infection induces a positive acute phase apolipoprotein E response from a negative acute phase gene: role of hepatic LDL receptors*

Thompson

Kitchens

2008

Journal of Lipid Research

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Apolipoprotein E (apoE) plays important roles in lipid homeostasis, anti-inflammation, and host defense. Since tissue apoE mRNA levels have been reported to decrease during inflammatory responses, we were surprised to find that plasma apoE levels were significantly elevated during septic infections in both humans and mice. This apparent paradox was also observed during lipopolysaccharideinduced acute inflammation in mice: plasma levels of apoE increased up to 4-fold despite sharply decreased apoE gene expression in the liver, macrophages, and extrahepatic tissues. We hypothesized that apoE levels were augmented by decreased plasma clearance. Our analysis revealed that apoE associated principally with HDL in mice and that apoE was cleared from the circulation principally via LDL receptors. The acute inflammatory response decreased LDL receptor expression in the liver and significantly reduced the rate of apoE clearance. In contrast, the same inflammatory stimuli increased LDL receptor expression in macrophages. Our results define a novel acute phase mechanism that increases circulating apoE levels as apoE production decreases. Diminished hepatic LDL receptor expression may thus cooperate with elevated LDL receptor expression in macrophages to facilitate the forward transport of apoE and its associated lipids to these key defense cells.

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Section: Discussionmentioning

confidence: 83%

Infection induces a positive acute phase apolipoprotein E response from a negative acute phase gene: role of hepatic LDL receptors*

Thompson

Kitchens

2008

Journal of Lipid Research

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“…High levels of human apo-B mRNA in transgenic liver undoubtedly result in high levels of human apo-B synthesis and secretion. In addition to increased synthesis, the human apo-B100-containing LDL in the transgenic mice may not be cleared rapidly from the circulation; in vitro binding studies using mouse fibroblasts have demonstrated that human apo-B100 binds poorly to the mouse LDL receptor (39). Thus, retarded clearance of human apo-B100 from transgenic mouse plasma may play a role in the high plasma concentrations of human apo-B 100.…”

Section: Discussionmentioning

confidence: 99%

Transgenic mice expressing high plasma concentrations of human apolipoprotein B100 and lipoprotein(a).

Linton¹,

Farese²,

Chiesa³

et al. 1993

J. Clin. Invest.

221

193

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The B apolipoproteins, apo-B48 and apo-B100, are key structural proteins in those classes of lipoproteins considered to be atherogenic [e.g., chylomicron remnants, ,f-VLDL, LDL, oxidized LDL, and Lp(a)J. Here we describe the development of transgenic mice expressing high levels of human apo-B48 and apo-B100. A 79.5-kb human genomic DNA fragment containing the entire human apo-B gene was isolated from a P1 bacteriophage library and microinjected into fertilized mouse eggs. 16 transgenic founders expressing human apo-B were generated, and the animals with the highest expression had plasma apo-B100 levels nearly as high as those of normolipidemic humans (-50 mg/dl). The human apo-B100 in transgenic mouse plasma was present largely in lipoproteins of the LDL class as shown by agarose gel electrophoresis, chromatography on a Superose 6 column, and density gradient ultracentrifugation. When the human apo-B transgenic founders were crossed with transgenic mice expressing human apo(a), the offspring that expressed both transgenes had high plasma levels of human Lp(a). Both the human apo-B and Lp(a) transgenic mice will be valuable resources for studying apo-B metabolism and the role of apo-B and Lp(a) in atherosclerosis. (J. Clin. Invest. 1993. 92:3029-3037.) Key words: P1 bacteriophage -low density lipoproteins * cholesterol

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“…Although studies have suggested that production rather than clearance rates are the most important determinants of apo (a) concentration in humans (36,37), variability in the levels of apo(a) (Lp[a]) in the transgenic mice are not likely to be determined at the level of production because of the lack of regulatory elements and the identical cDNA transgene in all mice. Human apoB has been shown to have a reduced interaction with the mouse LDL receptor (38) so it is conceivable that in our apoB/apo(a) transgenic model, apo(a) was increased in proportion to increased apoB because of inefficient clearance by the mouse LDL receptor of human apoB (and Lp[a]) particles and possibly competition of Lp(a) with apoB containing particles for clearance. The influence of apoB plasma levels on Lp(a) levels in humans is suggested by evidence that abetalipoproteinemic patients who lack plasma apoB tend to have lower apo(a) concentrations (39).…”

Section: Discussionmentioning

confidence: 99%

Atherogenesis in transgenic mice with human apolipoprotein B and lipoprotein (a).

Callow¹,

Verstuyft²,

Tangirala³

et al. 1995

J. Clin. Invest.

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Ability of the LDL receptor from several animal species to recognize the human apo B binding domain: studies with LDL from familial defective apo B-100

Cited by 30 publications

References 32 publications

Infection induces a positive acute phase apolipoprotein E response from a negative acute phase gene: role of hepatic LDL receptors*

Infection induces a positive acute phase apolipoprotein E response from a negative acute phase gene: role of hepatic LDL receptors*

Transgenic mice expressing high plasma concentrations of human apolipoprotein B100 and lipoprotein(a).

Atherogenesis in transgenic mice with human apolipoprotein B and lipoprotein (a).

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