Effect of lipid-bound apoA-I cysteine mutants on lipopolysaccharide-induced endotoxemia in mice

Abstract

HDL has been shown to be able to neutralize the toxicity of lipopolysaccharide (LPS). Our previous study ( J. Lipid Res. 2005. 46: 1303-1311 characterized the properties of secondary structure and in vitro functions of different cysteine mutants of apolipoprotein A-I. Here, we reconstituted recombinant HDLs (named rHDLwt, rHDL52, rHDL74, rHDL107, rHDL129, rHDL173, rHDL195, and rHDL228) by mixing wild type or those mutants with dipalmitoyl phosphatidylcholine and examined their in vivo effects on LPS-induced endotoxemia in mice. Our results showed that 24 h after injection, mice receiving rHDL74 or rHDL52 had a significant decrease of plasma tumor necrosis factor a (TNF-a) and interleukin-1b (IL-1b), compared with control mice receiving either saline or rHDLwt (P , 0.05). Administration of rHDL74 to mice injected with LPS also led to a decrease of plasma IL-6, protection of lung against acute injury, and attenuation of endotoxin-induced clinical symptoms in mice, compared with controls injected with LPS only. However, injection of rHDL228 significantly increased plasma concentration of TNF-a and exacerbated LPS-induced lung injury. In summary, compared with rHDLwt, rHDL74 and rHDL52 exhibit higher anti-inflammation capabilities, whereas rHDL228 shows hyper-proinflammation by exacerbating LPS-induced endotoxemia in mice.-Wang, Y., X. Zhu, G. Wu, L. Shen, and B. Chen. Effect of lipid-bound apoA-I cysteine mutants on lipopolysaccharide-induced endotoxemia in mice.

The role of HDL in innate immunity

“…Apolipoprotein A-I alone can neutralize LPS and this interaction can be altered by changing the structure of apolipoprotein A-I ( 18 ). For example, serine substitution of one cysteine (228) in the C-terminal domain dramatically reduces the ability of HDL to neutralize LPS, whereas substitutions of other cysteines (52 or 74) enhance the ability of HDL to neutralize LPS ( 18 ). The amino acid substitutions that affect LPS neutralization have minimal effects on the lipid composition of HDL.…”

Enantioselective Dehydroxylation of Enterodiol and Enterolactone Precursors by Human Intestinal Bacteria

“…[3][4][5][6][7][8][9] In particular, the biotransformation of plant lignans, such as secoisolariciresinol diglucoside (SDG), pinoresinol diglucoside (PDG), arctiin, and matairesinol to mammalian lignans, enterodiol (END, 1) and enterolactone (ENL, 2) have extensively been studied. The metabolic processes by intestinal bacteria include deglucosylation, ring cleavage, demethylation, dehydroxylation and oxidation.…”

HDL and innate immunity: a tale of two apolipoproteins

“…One of the key defensive functions is the ability of HDL and other lipoproteins to bind endotoxin (lipopolysaccharide, LPS) and other bacterial products and neutralize their toxic effects. In this issue of the Journal of Lipid Research, Wang et al (2) provide insights into the structural requirements for LPS neutralization by apolipoprotein A-I.…”

“…Thus, Wang et al (2) have shown that, as with cholesterol and phospholipid metabolism, specific regions of apolipoprotein A-I are essential for LPS neutralization. Furthermore, the regions involved in LPS neutralization are different than those involved in cholesterol and phospholipid metabolism.…”

“…The paper by Wang et al (2) addresses what regions of apolipoprotein A-I are required for neutralization of LPS by substituting other amino acids for specific cysteine residues. Serine substitution of one cysteine (228) in the C-terminal domain dramatically reduced the ability of HDL to neutralize LPS, while another C-terminal substitution (cysteine 195), proximal to the last 22 residue repeat, had little effect.…”