HUMAN RECOMBINANT APOLIPOPROTEIN-E REDIRECTS LIPOPOLYSACCHARIDE FROM KUPFFER CELLS TO LIVER PARENCHYMAL-CELLS IN RATS IN-VIVO

Chylomicrons have been shown to protect mice and rats against a lethal dose of lipopolysaccharide and may serve as a therapeutic means to pr otect against endotoxemia. However, the requisite of isolation from hu man lymph hampers pharmaceutical application, Recently, we developed r ecombinant chylomicrons from commercially available lipids and human r ecombinant apolipoprotein E. The current study explored the effectiven ess of these apoE-enriched emulsions in redirecting LPS from Kupffer c ells to liver parenchymal cells. Upon injection into rats, I-125-LPS r apidly and specifically associated with the liver (64.3 +/- 3.1% of th e injected dose) and spleen (4.1 +/- 0.7%), The uptake of LPS by the s pleen was four- to fivefold reduced upon incubation with the apoE-enri ched emulsion or free apoE (P < 0.0001), but not with emulsion alone o r Lipofundin. Within the liver, I-125-LPS mainly associated with Kupff er cells. The uptake by Kupffer cells was eight- to ninefold reduced b y the apoE-enriched emulsion or apoE alone (P < 0.01), and a 19.6-fold increased uptake ratio by liver parenchymal cells over Kupffer cells was observed, The emulsion without apoE had no effect on the in vivo k inetics of LPS. LPS interacted selectively with the apoE moiety of the recombinant chylomicron. Emulsion-associated and free apoE bound appr oximately two molecules of LPS, possibly by its exposed hydrophilic do main involving arginine residues. We anticipate that the protecting ef fect of endogenous chylomicrons against LPS-induced endotoxemia may re sult from the apoE moiety and that human recombinant apoE may serve as a therapeuticum to protect against endotoxemia.