Sepsis increases endocytosis of endotoxin into hepatocytes.
BACKGROUND
Chylomicrons bind endotoxins and accelerate their clearance from plasma to the liver. This results in reduced mortality from septic shock in a rodent model. We hypothesized that the clearance of the LPS-chylomicron (LPS-CM) complex by hepatocytes is due to receptor-mediated endocytosis and that sepsis up-regulates this process.


METHODS
Three groups of Sprague-Dawley rats; (1) control; (2) pretreated with 10 micrograms/kg LPS 24 hours before treatment; and (3) pretreated with 17-alpha-ethinyl estradiol (EE, 5 mg/kg subcutaneously for 3 days), were infused with labeled I125-LPS alone or with I125-LPS bound to chylomicron. Livers were removed 2.5, 15, and 30 minutes after LPS injection, and hepatic endosomes were isolated from the liver homogenates by serial ultracentrifugation in sucrose gradients.


RESULTS
The injection of I125-LPS-CM complexes resulted in higher levels of endosomal I125-LPS in all groups, as compared with I125-LPS alone. In addition, the endosomal uptake of I125-LPS was markedly increased by both LPS and EE pretreatments.


CONCLUSIONS
These data strongly suggest a primary role for receptor-mediated endocytosis in the increased clearance of LPS when bound to chylomicron. In addition, exposure to LPS appears to increase the accumulation of LPS in endosomes by a mechanism similar to that of EE, which is known to up-regulate receptor-mediated lipoprotein uptake. This endogenous pathway for the catabolism of endotoxins may provide a teleological explanation for the hypertriglyceridemia observed during sepsis.
Ghermay
A P
AP
Department of Surgery, VA Medical Center of San Francisco 94121, USA.
Brady
S
S
Havel
R J
RJ
Harris
H W
HW
Rapp
J H
JH
D000818:Animals; D002914:Chylomicrons / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000737:chemistry / Q000187:drug effects; D004731:Endotoxins / Q000378:metabolism*; D004997:Ethinyl Estradiol / Q000494:pharmacology; D007457:Iodine Radioisotopes; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000276:immunology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000378:metabolism; D018805:Sepsis / Q000503:physiopathology*; D015854:Up-Regulation / Q000187:drug effects
D002914:Chylomicrons; D004731:Endotoxins; D007457:Iodine Radioisotopes; D008070:Lipopolysaccharides; D011973:Receptors, LDL; D004997:Ethinyl Estradiol