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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1852

Article

Petropoulou, Peristera-Ioanna¹  Berbee, Jimmy F. P.¹  Theodoropoulos, Vassilios¹  Hatziri, Aikaterini¹  Stamou, Panagiota²  Karavia, Eleni A.¹  Spyridonidis, Alexandros²  Karagiannides, Iordanes^1,3  Kypreos, Kyriakos E.¹ 

[1] Univ Patras, Sch Med, Dept Pharmacol, Rio Achaias 26500, TK, Greece

[2] Univ Patras, Sch Med, Dept Hematol, Rio Achaias 26500, TK, Greece

[3] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Inflammatory Bowel Dis Ctr,Neuroendocrine Assay C, Los Angeles, CA 90095 USA

关键词: Lecithin-cholesterol acyltransferase;    Apolipoprotein A-I;    High-density lipoprotein;    LPS;    Inflammation;    Mice;   

DOI  :  10.1016/j.bbadis.2015.07.010

来源: Elsevier

【 摘 要 】

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 (100 mu g/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 (1-100 ng/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 TNF alpha. 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 TNFa 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. (C) 2015 Elsevier B.V. All rights reserved.

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