Hepatic uptake and deacylation of the LPS in bloodborne LPS-lipoprotein complexes

Abstract

Much evidence indicates that bacterial LPS (endotoxin) is removed from the bloodstream mainly by the liver, yet the hepatic uptake mechanisms remain uncertain and controversial. In plasma, LPS can be either ‘free’ (as aggregates, bacterial membrane fragments or loosely bound to albumin, CD14, or other proteins) or ‘bound’ (complexed with lipoproteins). Whereas most free LPS is taken up by Kupffer cells (KCs), lipoprotein-bound LPS has seemed to be cleared principally by hepatocytes. Here, we compared the liver’s ability to take up and deacylate free LPS aggregates and the LPS in preformed LPS-high density lipoprotein (HDL) complexes. In mice examined from 1 h to 7 d after a small amount of fluorescent (FITC-)LPS was injected into a lateral tail vein, we found FITC-LPS almost entirely within, or adjacent to, KCs. As expected, FITC-LPS complexed with HDL (FITC-LPS-HDL) disappeared more slowly from the circulation and a smaller fraction of the injected dose of FITC-LPS was found in the liver. Unexpectedly, the FITC-LPS injected as FITC-LPS-HDL complexes was also found within sinusoids, adjacent to, or within, KCs. In other experiments, we found that both free and HDL-bound radiolabeled LPS underwent enzymatic deacylation by acyloxyacyl hydrolase (AOAH), the LPS-inactivating enzyme that is principally produced within the liver by KCs. Our observations suggest that KCs and AOAH play important roles in clearing and catabolizing both free LPS and the LPS in circulating LPS-HDL complexes.

Blood-Borne Lipopolysaccharide Is Rapidly Eliminated by Liver Sinusoidal Endothelial Cells via High-Density Lipoprotein

“…Typhimurium PR122 (Rc) LPS(11), both are rough form of LPS with predicted labeling positions (Fig S1). The clearance kinetics of intravenously infused LPS was plotted based on the disappearance of 488-LPS (Fig 1) and decay of β-irradiation from peripheral blood measured periodically over 60 min (Fig.…”

“…Macrophages in general are thought to dephosphorylate and deacylate lipid A after phagocytosis(10,11) inactivating LPS. Although such enzymatic mechanisms appear to be well established, macrophage-mediated uptake and modification of LPS-lipid A happens slowly, typically over hours.…”

Lipopolysaccharide Clearance, Bacterial Clearance, and Systemic Inflammatory Responses Are Regulated by Cell Type–Specific Functions of TLR4 during Sepsis

“…Both Kupffer cells (49,50) and hepatocytes (9,(51)(52)(53) were shown to participate in LPS clearance. A specific pathway for LPS deacylation in Kupffer cells was identified (54). Other work showed that LPS can interact with low-density lipoproteins, which leads to the uptake of the complex by the lowdensity lipoprotein receptor (55,56).…”

The Role of the Liver in Sepsis

“…Hepatocytes also contribute to LPS clearance by primarily using lipoprotein. LPS-binding protein transfers LPS to CD14, thus facilitating the interaction between LPS and TLR4 on the surface of phagocytes to remove LPS and initiate the pro-inflammatory cascade [44]. In one study, TLR4 knockout murine hepatocytes failed to clear LPS, resulting in augmented inflammation and organ injury in both polymicrobial sepsis and endotoxemia [36].…”