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Lipoprotein Lipase Modulates Bone Marrow Myeloid Cell Proliferation by Affecting Colony‐Stimulating Factor Levels and Recruitment
Author(s) -
Chang Chuchun Liz,
Goldberg Ira J,
Deckelbaum Richard J
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.431.2
Subject(s) - lipoprotein lipase , myelopoiesis , endocrinology , medicine , lipolysis , macrophage , monocyte , biology , myeloid , bone marrow , inflammation , lipid metabolism , chemistry , immunology , microbiology and biotechnology , adipose tissue , biochemistry , stem cell , haematopoiesis , in vitro
Although inflammation is the body's basic response to ameliorate injury or infection, tissue macrophage‐mediated pro‐inflammatory responses promote metabolic diseases, such as atherosclerosis. Lipoprotein lipase (LpL) is the rate‐limiting enzyme that hydrolyzes circulating lipoprotein triglycerides (TG) to release free fatty acids. We have reported that loss of LpL expression reduced numbers of aortic macrophages and bone marrow (BM) myelopoiesis. Reconstitution of LpL‐expressing BM was able to replenish aortic macrophage density. Our current studies are directed toward understanding the molecular regulation of LpL in orchestrating lipoprotein metabolism and immune cell biology. Our data show that reduced aortic macrophage levels were associated with reduced blood white cells and leukocyte subsets, including macrophage precursor cells‐ monocytes. BM‐derived monocyte differentiation to macrophages was markedly reduced by 40% in the absence of LpL (p<0.05). We speculate that defective lipid metabolism induced by LpL deficiency can contribute to decreased BM myelopoiesis. In transgenic LpL knockout mice that are rescued from neonatal death by muscle‐specific LpL expression (MCKL0 mice), loss of LpL reduced BM monocyte/macrophage precursor (BMMP) cell TG uptake and accumulation by 22% and 50% (p<0.05), respectively. TG utilization was much lower (~40%) in MCKL0 BMMP cells compared to wild type (WT) BMMP cells. LpL deficiency significantly decreased BM expression of both macrophage‐colony‐stimulating factor (M‐CSF) and its receptor (M‐CSF‐R), required for myeloid cell proliferation and differentiation (p<0.05). LpL‐mediated lipolysis products (e.g., oleic acid) were able to stimulate expression of M‐CSF and M‐CSF‐R by > 35% (p<0.05) in WT BMMP cells. In addition, LpL and heparin, which releases LpL from the cell surface, modulated binding of M‐CSF to M‐CSF‐R in the immunobinding assay (p<0.05). We hypothesize that LpL also anchors M‐CSF to its receptor and triggers a series of downstream signaling pathways to stimulate monocyte differentiation to macrophages. We thus propose that LpL, in addition to being a lipolytic enzyme, also influences peripheral and BM immune cell responses. These studies provide valuable insight into the regulation of adverse inflammatory responses and have therapeutic applications for various blood cell diseases.