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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.

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Pharmacology Department, University of Patras Medical School, Rio Achaias TK. 26500, Greece.
Hematology Department, University of Patras Medical School, Rio Achaias, TK. 26500, Greece.
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.
Pharmacology Department, University of Patras Medical School, Rio Achaias TK. 26500, Greece. Electronic address:


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.


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

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