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Effects of deletion of macrophage ABCA7 on lipid metabolism and the development of atherosclerosis in the presence and absence of ABCA1.

Meurs I, Calpe-Berdiel L, Habets KL, Zhao Y, Korporaal SJ, Mommaas AM, Josselin E, Hildebrand RB, Ye D, Out R, Kuiper J, Van Berkel TJ, Chimini G, Van Eck M - PLoS ONE (2012)

Bottom Line: However, single deletion of ABCA1 had a similar effect (1.8-fold, p<0.05).In conclusion, deletion of ABCA7 in bone marrow-derived cells does not affect atherogenesis in the arterial wall neither in the absence or presence of ABCA1.Interestingly, combined deletion of bone marrow ABCA1 and ABCA7 causes severe splenomegaly associated with cellular lipid accumulation, a reduction in splenic CD3+ T cells, and induced markers of erythropoeisis.

View Article: PubMed Central - PubMed

Affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands.

ABSTRACT
ABCA7, a close relative of ABCA1 which facilitates cholesterol efflux to lipid-poor apoproteins, has been implicated in macrophage lipid efflux and clearance of apoptotic cells in in vitro studies. In the current study, we investigated the in vivo effects of macrophage ABCA7 deficiency on lipid metabolism and atherosclerosis. Chimeras with dysfunctional ABCA7 in macrophages and other blood cells were generated by transplantation of bone marrow from ABCA7 knockout (KO) mice into irradiated low-density lipoprotein receptor (LDLr) KO mice. Unexpectedly, macrophage ABCA7 deficiency did not significantly affect atherosclerosis susceptibility of LDLr KO mice after 10 weeks Western-type diet feeding. However, ABCA7 deficiency was associated with 2-fold (p<0.05) higher macrophage ABCA1 mRNA expression levels. Combined disruption of ABCA1 and ABCA7 in bone-marrow-derived cells increased atherosclerotic lesion development (1.5-fold (p>0.05) as compared to wild type transplanted mice. However, single deletion of ABCA1 had a similar effect (1.8-fold, p<0.05). Macrophage foam cell accumulation in the peritoneal cavity was reduced in ABCA1/ABCA7 dKO transplanted animals as compared to single ABCA1 KO transplanted mice, which was associated with increased ABCG1 expression. Interestingly, spleens of ABCA1/ABCA7 double KO transplanted mice were significantly larger as compared to the other 3 groups and showed massive macrophage lipid accumulation, a reduction in CD3+ T-cells, and increased expression of key regulators of erythropoiesis. In conclusion, deletion of ABCA7 in bone marrow-derived cells does not affect atherogenesis in the arterial wall neither in the absence or presence of ABCA1. Interestingly, combined deletion of bone marrow ABCA1 and ABCA7 causes severe splenomegaly associated with cellular lipid accumulation, a reduction in splenic CD3+ T cells, and induced markers of erythropoeisis. Our data indicate that ABCA7 may play a role in T cell proliferation and erythropoeisis in spleen.

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Effects of single macrophage ABCA7 and combined macrophage ABCA1 and ABCA7 deficiency on spleen.(A) Relative spleen weights of transplanted mice to body weight (bw) and representative images are shown. (B) Cryosections of spleens from all groups of mice were stained for lipid accumulation using Oil-red O staining (original magnification ×50 for first row and ×400 for second row), against lymphocyte CD3 antigen by immunohistochemistry (original magnification ×40) and for apoptosis using TUNEL staining (original magnification ×40). (C) Lipids were extracted from spleens with organic solvents. Values represent the mean±SEM of ≥9 mice per group. Statistically significant difference **p<0.01 and ***p<0.001. (D) Electron microscopic images of spleens from WT and dKO mice. Macrophages (mφ) of dKO transplanted mice exhibited massive cytoplasmic lipid accumulation (*).
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pone-0030984-g006: Effects of single macrophage ABCA7 and combined macrophage ABCA1 and ABCA7 deficiency on spleen.(A) Relative spleen weights of transplanted mice to body weight (bw) and representative images are shown. (B) Cryosections of spleens from all groups of mice were stained for lipid accumulation using Oil-red O staining (original magnification ×50 for first row and ×400 for second row), against lymphocyte CD3 antigen by immunohistochemistry (original magnification ×40) and for apoptosis using TUNEL staining (original magnification ×40). (C) Lipids were extracted from spleens with organic solvents. Values represent the mean±SEM of ≥9 mice per group. Statistically significant difference **p<0.01 and ***p<0.001. (D) Electron microscopic images of spleens from WT and dKO mice. Macrophages (mφ) of dKO transplanted mice exhibited massive cytoplasmic lipid accumulation (*).

Mentions: Both on chow and on WTD, WT, ABCA1 KO, ABCA7 KO, and dKO transplanted mice did not differ in body weight (data not shown). Furthermore, no differences in relative weight, lipid content and cell composition in liver, thymus, and lymph nodes were observed (data not shown). Interestingly, the relatively spleen weight of dKO transplanted mice was increased 3-fold (8.44±1.35 mg/g body weight (bw) compared with 2.70±0.14 mg/g bw in control mice; p<0.001) (Fig. 6A), while spleen weights of ABCA1 KO and ABCA7 KO transplanted mice did not differ compared to WT transplanted mice. In addition, macroscopically white foci were visible in spleens of dKO transplanted mice (Fig. 6A), which were consistent with lipid accumulation, visualized by Oil red-O staining of cryostat sections of the spleen (Fig. 6B). In agreement, lipid extraction analyses from the spleen showed a significant increase in TC and PL levels in dKO transplanted mice compared to WT (TC: 5.4-fold, p<0.001; PL: 1.9-fold, p<0.001), ABCA1 KO (TC: 19.7-fold, p<0.001; PL: 2.3-fold, p<0.001), and ABCA7 KO (TC: 9.4-fold, p<0.001; PL: 2.4-fold, p<0.001) transplanted mice (Fig. 6C). Electron microscopic analyses were performed to determine in which cell type and cellular compartment the accumulation of excessive amounts of lipid occured. Interestingly, massive cytoplasmic lipid accumulation was observed in the macrophages of dKO transplanted mice, which was not observed in spleens of WT transplanted mice (Fig. 6D).


Effects of deletion of macrophage ABCA7 on lipid metabolism and the development of atherosclerosis in the presence and absence of ABCA1.

Meurs I, Calpe-Berdiel L, Habets KL, Zhao Y, Korporaal SJ, Mommaas AM, Josselin E, Hildebrand RB, Ye D, Out R, Kuiper J, Van Berkel TJ, Chimini G, Van Eck M - PLoS ONE (2012)

Effects of single macrophage ABCA7 and combined macrophage ABCA1 and ABCA7 deficiency on spleen.(A) Relative spleen weights of transplanted mice to body weight (bw) and representative images are shown. (B) Cryosections of spleens from all groups of mice were stained for lipid accumulation using Oil-red O staining (original magnification ×50 for first row and ×400 for second row), against lymphocyte CD3 antigen by immunohistochemistry (original magnification ×40) and for apoptosis using TUNEL staining (original magnification ×40). (C) Lipids were extracted from spleens with organic solvents. Values represent the mean±SEM of ≥9 mice per group. Statistically significant difference **p<0.01 and ***p<0.001. (D) Electron microscopic images of spleens from WT and dKO mice. Macrophages (mφ) of dKO transplanted mice exhibited massive cytoplasmic lipid accumulation (*).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3293875&req=5

pone-0030984-g006: Effects of single macrophage ABCA7 and combined macrophage ABCA1 and ABCA7 deficiency on spleen.(A) Relative spleen weights of transplanted mice to body weight (bw) and representative images are shown. (B) Cryosections of spleens from all groups of mice were stained for lipid accumulation using Oil-red O staining (original magnification ×50 for first row and ×400 for second row), against lymphocyte CD3 antigen by immunohistochemistry (original magnification ×40) and for apoptosis using TUNEL staining (original magnification ×40). (C) Lipids were extracted from spleens with organic solvents. Values represent the mean±SEM of ≥9 mice per group. Statistically significant difference **p<0.01 and ***p<0.001. (D) Electron microscopic images of spleens from WT and dKO mice. Macrophages (mφ) of dKO transplanted mice exhibited massive cytoplasmic lipid accumulation (*).
Mentions: Both on chow and on WTD, WT, ABCA1 KO, ABCA7 KO, and dKO transplanted mice did not differ in body weight (data not shown). Furthermore, no differences in relative weight, lipid content and cell composition in liver, thymus, and lymph nodes were observed (data not shown). Interestingly, the relatively spleen weight of dKO transplanted mice was increased 3-fold (8.44±1.35 mg/g body weight (bw) compared with 2.70±0.14 mg/g bw in control mice; p<0.001) (Fig. 6A), while spleen weights of ABCA1 KO and ABCA7 KO transplanted mice did not differ compared to WT transplanted mice. In addition, macroscopically white foci were visible in spleens of dKO transplanted mice (Fig. 6A), which were consistent with lipid accumulation, visualized by Oil red-O staining of cryostat sections of the spleen (Fig. 6B). In agreement, lipid extraction analyses from the spleen showed a significant increase in TC and PL levels in dKO transplanted mice compared to WT (TC: 5.4-fold, p<0.001; PL: 1.9-fold, p<0.001), ABCA1 KO (TC: 19.7-fold, p<0.001; PL: 2.3-fold, p<0.001), and ABCA7 KO (TC: 9.4-fold, p<0.001; PL: 2.4-fold, p<0.001) transplanted mice (Fig. 6C). Electron microscopic analyses were performed to determine in which cell type and cellular compartment the accumulation of excessive amounts of lipid occured. Interestingly, massive cytoplasmic lipid accumulation was observed in the macrophages of dKO transplanted mice, which was not observed in spleens of WT transplanted mice (Fig. 6D).

Bottom Line: However, single deletion of ABCA1 had a similar effect (1.8-fold, p<0.05).In conclusion, deletion of ABCA7 in bone marrow-derived cells does not affect atherogenesis in the arterial wall neither in the absence or presence of ABCA1.Interestingly, combined deletion of bone marrow ABCA1 and ABCA7 causes severe splenomegaly associated with cellular lipid accumulation, a reduction in splenic CD3+ T cells, and induced markers of erythropoeisis.

View Article: PubMed Central - PubMed

Affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands.

ABSTRACT
ABCA7, a close relative of ABCA1 which facilitates cholesterol efflux to lipid-poor apoproteins, has been implicated in macrophage lipid efflux and clearance of apoptotic cells in in vitro studies. In the current study, we investigated the in vivo effects of macrophage ABCA7 deficiency on lipid metabolism and atherosclerosis. Chimeras with dysfunctional ABCA7 in macrophages and other blood cells were generated by transplantation of bone marrow from ABCA7 knockout (KO) mice into irradiated low-density lipoprotein receptor (LDLr) KO mice. Unexpectedly, macrophage ABCA7 deficiency did not significantly affect atherosclerosis susceptibility of LDLr KO mice after 10 weeks Western-type diet feeding. However, ABCA7 deficiency was associated with 2-fold (p<0.05) higher macrophage ABCA1 mRNA expression levels. Combined disruption of ABCA1 and ABCA7 in bone-marrow-derived cells increased atherosclerotic lesion development (1.5-fold (p>0.05) as compared to wild type transplanted mice. However, single deletion of ABCA1 had a similar effect (1.8-fold, p<0.05). Macrophage foam cell accumulation in the peritoneal cavity was reduced in ABCA1/ABCA7 dKO transplanted animals as compared to single ABCA1 KO transplanted mice, which was associated with increased ABCG1 expression. Interestingly, spleens of ABCA1/ABCA7 double KO transplanted mice were significantly larger as compared to the other 3 groups and showed massive macrophage lipid accumulation, a reduction in CD3+ T-cells, and increased expression of key regulators of erythropoiesis. In conclusion, deletion of ABCA7 in bone marrow-derived cells does not affect atherogenesis in the arterial wall neither in the absence or presence of ABCA1. Interestingly, combined deletion of bone marrow ABCA1 and ABCA7 causes severe splenomegaly associated with cellular lipid accumulation, a reduction in splenic CD3+ T cells, and induced markers of erythropoeisis. Our data indicate that ABCA7 may play a role in T cell proliferation and erythropoeisis in spleen.

Show MeSH
Related in: MedlinePlus