Secretion-recapture process of apolipoprotein E in hepatic uptake of chylomicron remnants in transgenic mice.

Shimano, Hitoshi; Namba, Yoshio; Ohsuga, Jun-ichi; Kawamura, Mitsuo; Yamamoto, Kazuki; Shimada, Masako; Gotoda, Takanari; Harada, Kenji; Yazaki, Yoshio; Yamada, Nobuhiro

doi:10.1172/jci117218

Cited by 53 publications

(44 citation statements)

References 34 publications

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“…1, was excised after agarose-electrophoresis, purified by extraction with phenol and chloroform, and used for microinjection. Transgenic mice was produced as previously described (12) embedded sections of the materials were subjected to immunohistochemistry as previously described (25). The primary antibodies used were a goat anti-human apoE antibody at 1:200.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of diet-induced atheroma formation in transgenic mice expressing apolipoprotein E in the arterial wall.

Shimano¹,

Ohsuga²,

Shimada³

et al. 1995

J. Clin. Invest.

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125

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Apolipoprotein E (apoE) plays a crucial role in lipoprotein metabolism both in plasma and in peripheral tissues. To test whether apoE in the vascular wall has a direct and local effect on atherogenesis, we established transgenic mice expressing human apoE under control of H2 Ld promoter. Studies on mRNA levels and immunohistochemistry demonstrated that this line was characterized by high expression of human apoE in the arterial wall while its expression was relatively low in other tissues as compared with the respective endogenous expression of mouse apoE. They showed no difference in plasma cholesterol levels and lipoprotein profile from controls when fed both normal and atherogenic diets. However, after 24 wk of an atherogenic diet, the formation of fatty streak lesions in proximal aorta was markedly inhibited in transgenic mice as compared with controls. Both lesion area and esterified cholesterol content were < 30% of those in controls. In a tissue cholesterol labeling study with 3H-cholesterol, the specific activity of aorta cholesterol was much less in transgenic mice, suggesting that apoE enhances cholesterol efflux from the aortic wall into plasma. Thus, apoE has anti-atherogenic action which is mediated via enhancing reverse cholesterol transport from arterial wall. (J. Clin. Invest. 1995.95:469-476.)

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Section: Methodsmentioning

confidence: 99%

Inhibition of diet-induced atheroma formation in transgenic mice expressing apolipoprotein E in the arterial wall.

Shimano¹,

Ohsuga²,

Shimada³

et al. 1995

J. Clin. Invest.

Self Cite

125

View full text Add to dashboard Cite

show abstract

“…infusion of apoE in cholesterol-fed rabbits and the demonstration of accelerated clearance of β-VLDL remnants from the blood and their uptake by the liver (10). In transgenic mice and rabbits, overexpression of apoE accelerated remnant clearance (11)(12)(13). Furthermore, apoE was localized to the sinusoids in the space of Disse, and after infusion of remnant lipoproteins, apoE disappeared from the sinusoids and appeared in hepatocytes (14).…”

Section: Role Of Apoe In Remnant Binding and Uptakementioning

confidence: 99%

Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing

Mahley¹,

Huang²

2007

J. Clin. Invest.

139

128

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“…Local hepatic expression of apo E has been proposed to promote receptor-mediated endocytosis by the LRP (20) or by both the LDLR and the LRP (14,18). Shimano et al reported that after the injection of human chylomicrons into transgenic mice overexpressing rat apo E in the liver, the density of apo E staining by immunocytochemistry at the basolateral surface of the hepatocyte decreased and there was an increase in vesicular staining in the cytoplasm, suggesting that apo E on the cell surface was used for the endocytosis of chylomicron remnants (21). However, definitive proof of the existence of the secretion-capture mechanism and demonstration of its physiologic relevance in vivo have been lacking.…”

Section: Introductionmentioning

confidence: 99%

Hepatic apo E expression is required for remnant lipoprotein clearance in the absence of the low density lipoprotein receptor.

Linton¹,

Hasty²,

Babaev³

et al. 1998

J. Clin. Invest.

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According to the secretion-capture model of remnant lipoprotein clearance, apo E secreted by hepatocytes into the space of Disse serves to enrich the remnants with a ligand for receptor-mediated lipoprotein endocytosis. Current evidence supports a two-receptor model of lipoprotein removal, in which apo E-containing remnants bind either the low density lipoprotein receptor (LDLR) or the LDLR-related protein (LRP). Recently, we demonstrated that reconstitution of apo E( Ϫ / Ϫ ) mice with apo E( ϩ / ϩ ) marrow results in normalization of plasma lipoprotein levels, indicating that hepatic expression of apo E is not required for remnant clearance and calling into question the relevance of the secretion-capture mechanism. To dissect the relative contributions of LDLR and LRP to the cellular catabolism of remnant lipoproteins by the hepatocyte, bone marrow transplantation (BMT) was used to reconstitute macrophage expression of apo E in mice that were null for expression of both apo E and the LDLR. Reconstitution of macrophage apo E in apo E( Ϫ / Ϫ )/LDLR( Ϫ / Ϫ ) mice had no effect on serum lipid and lipoprotein concentrations, although it produced plasma apo E levels up to 16-fold higher than in C57BL/6 controls. Immunocytochemistry of hepatic sections revealed abundant staining for apo E in the space of Disse, but no evidence of receptor-mediated endocytosis of remnant lipoproteins. Transient expression of human LDLR in the livers of apo E( ϩ / ϩ ) → apo E( Ϫ / Ϫ )/LDLR( Ϫ / Ϫ ) mice by adenoviral gene transfer resulted in normalization of serum lipid levels and in the clearance of apo E-containing lipoproteins from the space of Disse. We conclude that whereas the LDLR efficiently clears remnant lipoproteins irrespective of the site of origin of apo E, endocytosis by the chylomicron remnant receptor (LRP) is absolutely dependent on hepatic expression of apo E. These data demonstrate in vivo the physiologic relevance of the apo E secretion-capture mechanism in the liver. ( J. Clin. Invest. 1998. 101:1726-1736.)

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Secretion-recapture process of apolipoprotein E in hepatic uptake of chylomicron remnants in transgenic mice.

Cited by 53 publications

References 34 publications

Inhibition of diet-induced atheroma formation in transgenic mice expressing apolipoprotein E in the arterial wall.

Inhibition of diet-induced atheroma formation in transgenic mice expressing apolipoprotein E in the arterial wall.

Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing

Hepatic apo E expression is required for remnant lipoprotein clearance in the absence of the low density lipoprotein receptor.

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