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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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Plasma lipid levels and cholesterol lipoprotein distribution profile after 10 weeks WTD feeding of LDLr KO mice reconstituted with WT, ABCA1 KO, ABCA7 KO and dKO bone marrow.Blood samples were drawn after an overnight fast. (A) The concentrations of cholesterol, phospholipids and triglycerides in serum were determined using enzymatic colorimetric assays. (B) The distribution of cholesterol over the different lipoproteins was determined by fractionation of serum from individual mice using a Superose 6 column. Fractions 2 to 5 represent VLDL; fraction 6 to 14, LDL; and fractions 15 to 20, HDL, respectively. Values represent the mean±SEM of ≥6 mice per group. Statistically significant difference *p<0.05, **p<0.01, and *** p<0.001.
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pone-0030984-g002: Plasma lipid levels and cholesterol lipoprotein distribution profile after 10 weeks WTD feeding of LDLr KO mice reconstituted with WT, ABCA1 KO, ABCA7 KO and dKO bone marrow.Blood samples were drawn after an overnight fast. (A) The concentrations of cholesterol, phospholipids and triglycerides in serum were determined using enzymatic colorimetric assays. (B) The distribution of cholesterol over the different lipoproteins was determined by fractionation of serum from individual mice using a Superose 6 column. Fractions 2 to 5 represent VLDL; fraction 6 to 14, LDL; and fractions 15 to 20, HDL, respectively. Values represent the mean±SEM of ≥6 mice per group. Statistically significant difference *p<0.05, **p<0.01, and *** p<0.001.

Mentions: Bone marrow from WT, ABCA1 KO, ABCA7 KO, and dKO mice was transplanted into LDLr KO mice. From 8 weeks after bone marrow transplantation, the transplanted mice were challenged with the WTD to induce atherosclerotic lesion development. Similar as in the first BMT experiment, ABCA7 deletion in bone marrow-derived cells did not affect serum TC, TG or PL levels (Fig. 2A). However, in agreement with previous studies [30], deletion of ABCA1 in bone marrow cells resulted in significantly lower serum lipid levels compared to WT transplanted mice when fed WTD (TC: 0.5-fold; p<0.001, PL: 0.7-fold, p<0.001, TG: 0.5-fold, p<0.05). A similar decrease in serum lipids levels was found in LDLr KO mice transplanted with bone marrow lacking both ABCA1 and ABCA7 (TC: 0.4-fold; p<0.001, PL: 0.4-fold, p<0.001, TG: 0.2-fold; p<0.01).


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)

Plasma lipid levels and cholesterol lipoprotein distribution profile after 10 weeks WTD feeding of LDLr KO mice reconstituted with WT, ABCA1 KO, ABCA7 KO and dKO bone marrow.Blood samples were drawn after an overnight fast. (A) The concentrations of cholesterol, phospholipids and triglycerides in serum were determined using enzymatic colorimetric assays. (B) The distribution of cholesterol over the different lipoproteins was determined by fractionation of serum from individual mice using a Superose 6 column. Fractions 2 to 5 represent VLDL; fraction 6 to 14, LDL; and fractions 15 to 20, HDL, respectively. Values represent the mean±SEM of ≥6 mice per group. Statistically significant difference *p<0.05, **p<0.01, and *** p<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3293875&req=5

pone-0030984-g002: Plasma lipid levels and cholesterol lipoprotein distribution profile after 10 weeks WTD feeding of LDLr KO mice reconstituted with WT, ABCA1 KO, ABCA7 KO and dKO bone marrow.Blood samples were drawn after an overnight fast. (A) The concentrations of cholesterol, phospholipids and triglycerides in serum were determined using enzymatic colorimetric assays. (B) The distribution of cholesterol over the different lipoproteins was determined by fractionation of serum from individual mice using a Superose 6 column. Fractions 2 to 5 represent VLDL; fraction 6 to 14, LDL; and fractions 15 to 20, HDL, respectively. Values represent the mean±SEM of ≥6 mice per group. Statistically significant difference *p<0.05, **p<0.01, and *** p<0.001.
Mentions: Bone marrow from WT, ABCA1 KO, ABCA7 KO, and dKO mice was transplanted into LDLr KO mice. From 8 weeks after bone marrow transplantation, the transplanted mice were challenged with the WTD to induce atherosclerotic lesion development. Similar as in the first BMT experiment, ABCA7 deletion in bone marrow-derived cells did not affect serum TC, TG or PL levels (Fig. 2A). However, in agreement with previous studies [30], deletion of ABCA1 in bone marrow cells resulted in significantly lower serum lipid levels compared to WT transplanted mice when fed WTD (TC: 0.5-fold; p<0.001, PL: 0.7-fold, p<0.001, TG: 0.5-fold, p<0.05). A similar decrease in serum lipids levels was found in LDLr KO mice transplanted with bone marrow lacking both ABCA1 and ABCA7 (TC: 0.4-fold; p<0.001, PL: 0.4-fold, p<0.001, TG: 0.2-fold; p<0.01).

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