Hepatic endosomal trafficking of lipoprotein-bound endotoxin in rats.
Triglyceride-rich lipoproteins (chylomicrons (CM), VLDL) can bind and protect against endotoxin (LPS)-induced shock and mortality in rodents. The protective effect of lipoproteins is in part due to the increased plasma clearance and biliary excretion of LPS. Specifically, CM-LPS complexes are principally removed from the circulation by the liver with a rapid plasma half-life approximating that for CM alone. Thus, we hypothesized that hepatocytes clear CM-bound LPS via known lipoprotein receptors and traffic the toxic macromolecule through the same endosomal pathway employed for the catabolism of triglyceride-rich lipoproteins. To examine the endosomal uptake and biliary excretion of LPS, we isolated early and late hepatic endosomal fractions and hepatic bile from rats following the injection of radiolabeled CM-bound LPS. The uptake of (125)I-LPS was compared in animals that overexpressed either the LDL receptor or the LDL receptor-related protein (LRP) versus untreated control with normal lipoprotein levels. Herein we present data indicating that both the LDL receptor and the LRP participate in the rapid internalization of CM-bound LPS by hepatocytes. Upregulation of the LDL receptor increased the accumulation of (125)I-LPS in late endosomes (P < 0.03). In contrast, increased levels of the LRP were associated with negligible movement of LPS into late endosomes but a trend toward the increased biliary excretion of the radiolabeled macromolecule. Taken together these data further elucidate the role of the liver in the host innate immune response to infection and potentially implicate distinct roles for the LDL receptor and LRP in the catabolism of CM-bound LPS.
Department of Surgery, University of California at San Francisco, San Francisco, CA 94143, USA.
Hobart W
HW
Harris
Sandra E
SE
Brady
Joseph H
JH
Rapp
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001646:Bile / Q000378:metabolism; D002914:Chylomicrons / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D005682:Gadolinium / Q000494:pharmacology; D007457:Iodine Radioisotopes; D008070:Lipopolysaccharides / Q000097:blood / Q000493:pharmacokinetics*; D008074:Lipoproteins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D002914:Chylomicrons; D007457:Iodine Radioisotopes; D008070:Lipopolysaccharides; D008074:Lipoproteins; D011973:Receptors, LDL; D014280:Triglycerides; D005682:Gadolinium; C038958:gadolinium chloride