Apotipoprotein E Accelerates the Efflux of Cholesterol from Macrophages : Mechanism of Xanthoma Formation in Apolipoprotein E Deficiency

Kinoshita, Makoto; Kawamura, Mitsunobu; Maeda, Tomomi; Fujimaki, Yuko; Fujita, Masato; Kojima, Kosuke; Teramoto, Tamio

doi:10.5551/jat1994.6.22

Cited by 14 publications

(10 citation statements)

References 22 publications

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“…In addition, apoE is involved in both the assembly [13,14] and secretion [15,16] of very low-density lipoproteins (VLDLs) in hepatocytes. In macrophages, apoE also plays a critical role in cholesterol efflux [17][18][19][20]. Based on the multiple and critical roles for apoE in the metabolism of lipids and lipoproteins, we and others hypothesized and showed that a fraction of apoE internalized with lipoproteins escapes lysosomal degradation and is resecreted.…”

Section: Introductionmentioning

confidence: 99%

Physiological relevance of apolipoprotein E recycling: studies in primary mouse hepatocytes

et al. 2005

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Section: Introductionmentioning

confidence: 99%

Physiological relevance of apolipoprotein E recycling: studies in primary mouse hepatocytes

et al. 2005

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“…In addition, it is involved in both the assembly (13,14) and secretion (15,16) of VLDL. ApoE also plays a critical role in cholesterol efflux from macrophages (17)(18)(19)(20), a role that could be attributable to both intracellular and extracellular effects. Because apoE can easily transfer between lipoproteins and yet binds tightly to its receptors, we first hypothesized and later demonstrated that a substantial amount of internalized apoE escapes lysosomal degradation and is routed back (recycled) through the secretory pathway (21)(22)(23).…”

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confidence: 99%

Intracellular trafficking of recycling apolipoprotein E in Chinese hamster ovary cells

Braun

Mohler

Weisgraber

et al. 2006

Journal of Lipid Research

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We have investigated apolipoprotein E (apoE) recycling in Chinese hamster ovary (CHO) cells, a peripheral cell that does not produce lipoproteins or express apoE. Using a pulse-chase protocol in which cells were pulsed with 125 I-apoE-VLDL and chased for different periods, z30% of the apoE internalized during the pulse was resecreted within a 4 h chase in a relatively lipid-free state. The addition of lysosomotropic agents or brefeldin A had no effect on apoE recycling. Unlike previous results with hepatocytes and macrophages, neither apoA-I nor upregulation of ABCA1 stimulated apoE recycling. However, cyclodextrin, which extracts cholesterol from plasma membrane lipid rafts, increased recycling. Confocal studies revealed that apoE, internalized during a 1 h pulse, colocalizes with early endosomal antigen-1, Rab5, Rab11a, and lysobisphosphatidic acid but not with lysosomal-associated membrane protein-1. Colocalization of apoE and Rab11a persisted even after cells had been chased for 1 h, suggesting a pool of apoE within the endosomal recycling compartment (ERC). Our data suggest that apoE recycling in CHO cells is linked to cellular cholesterol removal via the ERC and phospholipidcontaining acceptors in a pathway alternative to the ABCA1-apoA-I axis.-Braun, N. A., P. J. Apolipoprotein E (apoE) is a 34 kDa protein that functions in plasma lipoprotein metabolism and intracellular lipid disposal. Extracellularly, apoE is a key mediator of the internalization of remnant lipoprotein particles by serving as a ligand for the LDL receptor (1, 2) and the low density lipoprotein receptor-related protein (LRP) (3, 4). ApoE is also internalized by binding heparan sulfate proteoglycans alone (5, 6) or via a mechanism involving both heparan sulfate proteoglycans and LRP (7,8). Intracellularly, apoE modulates lipid metabolism (9, 10) and functions in the routing of internalized lipoprotein remnants (11,12). In addition, it is involved in both the assembly (13, 14) and secretion (15, 16) of VLDL. ApoE also plays a critical role in cholesterol efflux from macrophages (17-20), a role that could be attributable to both intracellular and extracellular effects. Because apoE can easily transfer between lipoproteins and yet binds tightly to its receptors, we first hypothesized and later demonstrated that a substantial amount of internalized apoE escapes lysosomal degradation and is routed back (recycled) through the secretory pathway (21-23). We reported that apoE is found in the media of hepatocyte cultures from apoEdeficient mice transplanted with wild-type bone marrow (22), proof that systemic apoE can be retained by the liver cell and eventually resecreted. In addition, we reported that apoE was resecreted from apoE-deficient hepatocytes after incubation with apoE-containing VLDL (23). Furthermore, apoA-I stimulates apoE recycling in hepatocytes (23) and macrophages (24), suggesting a role for recycling in HDL metabolism. Finally, we have shown that apoE recycling occurs in the absence of the LDL receptor, under condition...

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“…In addition, it is involved in both the assembly (13,14) and secretion (15,16) of VLDLs. ApoE also plays a critical role in cholesterol efflux from macrophages (17)(18)(19)(20), a role that could be due to both intracellular and extracellular effects. Because apoE can easily transfer between lipoproteins and binds tightly to its receptors, we and others hypothesized and proved that a substantial amount of internalized apoE escapes lysosomal degradation and is routed into the secretory pathway.…”

mentioning

confidence: 99%

The recycling of apolipoprotein E and its amino-terminal 22 kDa fragment

Farkas

Weisgraber

Shepherd

et al. 2004

Journal of Lipid Research

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A portion of apolipoprotein E (apoE) internalized by hepatocytes is spared degradation and is recycled.To investigate the intracellular routing of recycling apoE, primary hepatocyte cultures from LDL receptor-deficient mice and mice deficient in receptor-associated protein [a model of depressed expression of LDL receptor-related protein (LRP)] were incubated with human VLDL containing 125 I-labeled human recombinant apoE3. Approximately 30% of the internalized intact apoE was recycled after 4 h. The N-terminal 22 kDa fragment of apoE was also resecreted, demonstrating that this apoE domain contains sufficient sequence to recycle. The 22 kDa fragment has reduced affinity for lipoproteins, suggesting that apoE recycling is linked to the ability of apoE to bind directly to a recycling receptor. Finally, apoE was found to recycle equally well in the presence of brefeldin A, a drug that blocks transport from the endoplasmic reticulum and leads to collapse of the Golgi stacks. Our studies demonstrate that apoE recycling occurs 1) in the absence of the LDL receptor or under conditions of markedly reduced LRP expression; 2) when apoE lacks the carboxyl-terminal domain, which allows binding to the lipoprotein; and 3) in the absence of an intact Golgi apparatus. We conclude that apoE recycling occurs through multiple redundant pathways. Apolipoprotein E (apoE) is a 34 kDa protein with functions in plasma lipoprotein metabolism and intracellular lipid disposal. Extracellularly, apoE is a key mediator of the internalization of lipoprotein particles, serving as a ligand for the LDL receptor (1, 2) and the LDL receptorrelated protein (LRP) (3, 4). ApoE is also internalized by binding heparan sulfate proteoglycans (HSPGs) alone (5, 6) or via a mechanism involving both HSPGs and LRP (7,8). Intracellularly, apoE modulates lipid metabolism (9, 10) and functions in the routing of internalized lipoprotein remnants (11,12). In addition, it is involved in both the assembly (13, 14) and secretion (15, 16) of VLDLs. ApoE also plays a critical role in cholesterol efflux from macrophages (17-20), a role that could be due to both intracellular and extracellular effects. Because apoE can easily transfer between lipoproteins and binds tightly to its receptors, we and others hypothesized and proved that a substantial amount of internalized apoE escapes lysosomal degradation and is routed into the secretory pathway.We have established that a portion of apoE internalized on triglyceride-rich lipoproteins, as well as on HDL, is spared degradation and recycled (21-23). We also demonstrated that internalized apoE is found in the media of hepatocyte cultures from apoE Ϫ / Ϫ mice transplanted with wild-type bone marrow (22), a proof that systemic apoE can be retained by the liver cell and is eventually regurgitated. In addition, we reported that apoE was resecreted from apoE Ϫ / Ϫ hepatocytes after incubation with apoEcontaining mouse VLDL (23). The fact that apoA-I stimulated apoE resecretion from hepatocytes suggests a role for recycling...

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Apotipoprotein E Accelerates the Efflux of Cholesterol from Macrophages : Mechanism of Xanthoma Formation in Apolipoprotein E Deficiency

Cited by 14 publications

References 22 publications

Physiological relevance of apolipoprotein E recycling: studies in primary mouse hepatocytes

Physiological relevance of apolipoprotein E recycling: studies in primary mouse hepatocytes

Intracellular trafficking of recycling apolipoprotein E in Chinese hamster ovary cells

The recycling of apolipoprotein E and its amino-terminal 22 kDa fragment

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