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Very-low and low-density lipoproteins induce neutral lipid accumulation and impair migration in monocyte subsets.

ABSTRACT: Blood monocytes are heterogeneous effector cells of the innate immune system. In circulation these cells are constantly in contact with lipid-rich lipoproteins, yet this interaction is poorly characterised. Our aim was to examine the functional effect of hyperlipidaemia on blood monocytes. In the Ldlr(-/-) mouse monocytes rapidly accumulate cytoplasmic neutral lipid vesicles during hyperlipidaemia. Functional analysis in vivo revealed impaired monocyte chemotaxis towards peritonitis following high fat diet due to retention of monocytes in the greater omentum. In vitro assays using human monocytes confirmed neutral lipid vesicle accumulation after exposure to LDL or VLDL. Neutral lipid accumulation did not inhibit phagocytosis, endothelial adhesion, intravascular crawling and transmigration. However, lipid loading led to a migratory defect towards C5a and disruption of cytoskeletal rearrangement, including an inhibition of RHOA signaling. These data demonstrate distinct effects of hyperlipidaemia on the chemotaxis and cytoskeletal regulation of monocyte subpopulations. These data emphasise the functional consequences of blood monocyte lipid accumulation and reveal important implications for treating inflammation, infection and atherosclerosis in the context of dyslipidaemia.

SUBMITTER: Jackson WD

PROVIDER: S-EPMC4731823 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Very-low and low-density lipoproteins induce neutral lipid accumulation and impair migration in monocyte subsets.

Jackson William D WD Weinrich Tobias W TW Woollard Kevin J KJ

Scientific reports 20160129

Blood monocytes are heterogeneous effector cells of the innate immune system. In circulation these cells are constantly in contact with lipid-rich lipoproteins, yet this interaction is poorly characterised. Our aim was to examine the functional effect of hyperlipidaemia on blood monocytes. In the Ldlr(-/-) mouse monocytes rapidly accumulate cytoplasmic neutral lipid vesicles during hyperlipidaemia. Functional analysis in vivo revealed impaired monocyte chemotaxis towards peritonitis following hi ...[more]

PMID: 26821597

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Project description:It is uncertain whether pharmacological reductions in very-low-density lipoproteins (VLDLs), and their component triglyceride and cholesterol could reduce residual risk of atherosclerotic cardiovascular disease (ASCVD) events among individuals in whom low-density lipoprotein cholesterol (LDL-C) has been adequately lowered. We examined whether individuals with greater on-statin reductions in VLDL-related measures-beyond reductions in LDL-C-were at further reduced risk of ASCVD. In 9423 participants in the JUPITER (Justification for the Use of Statins in Prevention) trial (NCT00239681), at baseline and on statin we measured standard lipids, 400-MHz proton nuclear magnetic resonance spectroscopy-measured VLDL particle subclasses (small, medium, and large VLDL lipoprotein particle concentration), and total VLDL cholesterol mass. Compared with individuals allocated to placebo, we examined risk of incident ASCVD (N=211) among statin-allocated participants who achieved minimal (<median) or greater (≥median) marker reductions using adjusted Cox models. On-statin changes in VLDL-related markers were only modestly correlated (Spearman r≤0.29) with change in LDL-C. On-statin median LDL-C was 54 mg/dL and triglyceride was 101 mg/dL. Dose-response reductions in ASCVD risk were observed for greater reductions in LDL-C, VLDL cholesterol mass, and small VLDL lipoprotein particle concentration; the latter 2 remained significant after incremental adjustment for change in LDL-C (P≤0.006). Conversely, there was no further risk reduction with greater reductions in triglycerides or large/medium VLDL lipoprotein particle concentration. Pharmacological reduction in small, cholesterol-enriched, triglyceride-depleted VLDL was associated with reduction in ASCVD risk. Chemically measured triglycerides may not sufficiently capture risk related to VLDL pathways. These findings also support broader profiling of lipid and lipoprotein changes in response to statins as prognostic markers of individual benefit, supporting more precision-medicine, individualized approaches to cardiovascular risk reduction. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Dataset Information

Very-low and low-density lipoproteins induce neutral lipid accumulation and impair migration in monocyte subsets.

Publications

Very-low and low-density lipoproteins induce neutral lipid accumulation and impair migration in monocyte subsets.

Similar Datasets

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