Apolipoprotein CI stimulates the response to lipopolysaccharide and reduces mortality in gram-negative sepsis.

Gram-negative sepsis is a major death cause in intensive care units. Accumulating evidence indicates the protective role of plasma lipoproteins such as high-density lipoprotein (HDL) in sepsis. It has recently been shown that septic HDL is almost depleted from apolipoprotein CI (apoCI), suggesting that apoCI may be a protective factor in sepsis. Sequence analysis revealed that apoCI possesses a highly conserved consensus KVKEKLK binding motif for lipopolysaccharide (LPS), an outer-membrane component of gram-negative bacteria. Through avid binding to LPS involving this motif, apoCI improved the presentation of LPS to macrophages in vitro and in mice, thereby stimulating the inflammatory response to LPS. Moreover, apoCI dose-dependently increased the early inflammatory response to Klebsiella pneumoniae-induced pneumonia, reduced the number of circulating bacteria, and protected mice against fatal sepsis. Our data support the hypothesis that apoCI is a physiological protector against infection by enhancing the early inflammatory response to LPS and suggest that timely increase of apoCI levels could be used to efficiently prevent and treat early sepsis.

Metabolism of apolipoprotein C-III in normolipemic human subjects.

Radioiodinated apolipoprotein C-III labeled either by the iodine monochloride procedure or by the Bolton-Hunter reagent were incubated in vitro with normal HDL. The labeled HDL-apo C-III, after ultracentrifugation and dialysis, was injected intravenously in 8 normolipidemic subjects. The label was followed in VLDL, IDL + LDL, HDL, d = 1.225 g/ml infranate as well as in total plasma and urine for the first time over a period of 2 weeks. Apolipoprotein C-III distributes readily between the different lipoprotein classes, only a small amount being present in the non-lipoprotein fraction. The percent distribution of apo C-III radioactivity and mass was found similar in VLDL, IDL and HDL using 3 different separation methods. Residence time in the whole system was 2.45 +/- 0.33 days. Fractional catabolic rates calculated from the urine/plasma radioactivity ratios or from the plasma curve were 0.731 +/- 0.096 and 0.767 +/- 0.125 pools/day. Synthetic rate was 2.28 +/- 0.32 mg/day/kg. The parameters seem not affected by the labeling procedure. The shapes of the plasma curve and of the urine/plasma ratio curve suggest a kinetic heterogeneity in the metabolism of apo C-III-containing particles.