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Lipoprotein Lipase Deficiency Impairs Bone Marrow Myelopoiesis and Reduces Circulating Monocyte Levels
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
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2018 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 38, no 3, p. 509-519Article in journal (Refereed) Published
Abstract [en]

Objective: Tissue macrophages induce and perpetuate proinflammatory responses, thereby promoting metabolic and cardiovascular disease. Lipoprotein lipase (LpL), the rate-limiting enzyme in blood triglyceride catabolism, is expressed by macrophages in atherosclerotic plaques. We questioned whether LpL, which is also expressed in the bone marrow (BM), affects circulating white blood cells and BM proliferation and modulates macrophage retention within the artery.

Approach and Results: We characterized blood and tissue leukocytes and inflammatory molecules in transgenic LpL knockout mice rescued from lethal hypertriglyceridemia within 18 hours of life by muscle-specific LpL expression (MCKL0 mice). LpL-deficient mice had ≈40% reduction in blood white blood cell, neutrophils, and total and inflammatory monocytes (Ly6C/Ghi). LpL deficiency also significantly decreased expression of BM macrophage-associated markers (F4/80 and TNF-α [tumor necrosis factor α]), master transcription factors (PU.1 and C/EBPα), and colony-stimulating factors (CSFs) and their receptors, which are required for monocyte and monocyte precursor proliferation and differentiation. As a result, differentiation of macrophages from BM-derived monocyte progenitors and monocytes was decreased in MCKL0 mice. Furthermore, although LpL deficiency was associated with reduced BM uptake and accumulation of triglyceride-rich particles and macrophage CSF–macrophage CSF receptor binding, triglyceride lipolysis products (eg, linoleic acid) stimulated expression of macrophage CSF and macrophage CSF receptor in BM-derived macrophage precursor cells. Arterial macrophage numbers decreased after heparin-mediated LpL cell dissociation and by genetic knockout of arterial LpL. Reconstitution of LpL-expressing BM replenished aortic macrophage density.

Conclusions: LpL regulates peripheral leukocyte levels and affects BM monocyte progenitor differentiation and aortic macrophage accumulation.

Place, publisher, year, edition, pages
2018. Vol. 38, no 3, p. 509-519
Keywords [en]
bone marrow, colony-stimulating factors, hematopoiesis, leukocytosis, lipoprotein lipase, crophages, monocytes
National Category
Cardiac and Cardiovascular Systems Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-145575DOI: 10.1161/ATVBAHA.117.310607ISI: 000425754700008PubMedID: 29371243OAI: oai:DiVA.org:umu-145575DiVA, id: diva2:1192229
Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-06-09Bibliographically approved

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Nyrén, RakelOlivecrona, Gunilla

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Arteriosclerosis, Thrombosis and Vascular Biology
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