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Biochim Biophys Acta. 2015 Oct;1852(10 Pt A):2106-15. doi: 10.1016/j.bbadis.2015.07.010. Epub 2015 Jul 10.

Lack of LCAT reduces the LPS-neutralizing capacity of HDL and enhances LPS-induced inflammation in mice.

Author information

1
Pharmacology Department, University of Patras Medical School, Rio Achaias TK. 26500, Greece.
2
Hematology Department, University of Patras Medical School, Rio Achaias, TK. 26500, Greece.
3
Pharmacology Department, University of Patras Medical School, Rio Achaias TK. 26500, Greece; Inflammatory Bowel Disease Center, Neuroendocrine Assay Core, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
4
Pharmacology Department, University of Patras Medical School, Rio Achaias TK. 26500, Greece. Electronic address: kkypreos@med.upatras.gr.

Abstract

HDL has important immunomodulatory properties, including the attenuation of lipopolysaccharide (LPS)-induced inflammatory response. As lecithin-cholesterol acyltransferase (LCAT) is a critical enzyme in the maturation of HDL we investigated whether LCAT-deficient (Lcat(-/-)) mice present an increased LPS-induced inflammatory response. LPS (100μg/kg body weight)-induced cytokine response in Lcat(-/-) mice was markedly enhanced and prolonged compared to wild-type mice. Importantly, reintroducing LCAT expression using adenovirus-mediated gene transfer reverted their phenotype to that of wild-type mice. Ex vivo stimulation of whole blood with LPS (1-100ng/mL) showed a similar enhanced pro-inflammatory phenotype. Further characterization in RAW 264.7 macrophages in vitro showed that serum and HDL, but not chylomicrons, VLDL or the lipid-free protein fraction of Lcat(-/-) mice, had a reduced capacity to attenuate the LPS-induced TNFα response. Analysis of apolipoprotein composition revealed that LCAT-deficient HDL lacks significant amounts of ApoA-I and ApoA-II and is primarily composed of ApoE, while HDL from Apoa1(-/-) mice is highly enriched in ApoE and ApoA-II. ApoA-I-deficiency did not affect the capacity of HDL to neutralize LPS, though Apoa1(-/-) mice showed a pronounced LPS-induced cytokine response. Additional immunophenotyping showed that Lcat(-/-) , but not Apoa1(-/-) mice, have markedly increased circulating monocyte numbers as a result of increased Cd11b(+)Ly6C(med) monocytes, whereas 'pro-inflammatory' Cd11b(+)Ly6C(hi) monocytes were reduced. In line with this observation, peritoneal macrophages of Lcat(-/-) mice showed a markedly dampened LPS-induced TNFα response. We conclude that LCAT-deficiency increases LPS-induced inflammation in mice due to reduced LPS-neutralizing capacity of immature discoidal HDL and increased monocyte number.

KEYWORDS:

Apolipoprotein A-I; High-density lipoprotein; Inflammation; LPS; Lecithin–cholesterol acyltransferase; Mice

PMID:
26170061
DOI:
10.1016/j.bbadis.2015.07.010
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