Endotoxin suppresses mouse hepatic low-density lipoprotein-receptor expression via a pathway independent of the toll-like receptor 4.
Endotoxin provokes an inflammatory state in the infected host. C3H/HeJ mice are tolerant to endotoxin because of an Lps gene mutation. Recent studies have identified that this gene encodes the Toll-like receptor 4. Endotoxin also induces hyperlipidemia and suppresses hepatic low-density lipoprotein (LDL)-receptor expression. In the current study, we investigated whether a defective Lps gene would impair the hepatic LDL-receptor response to endotoxin in C3H/HeJ mice. Eighteen hours after an intraperitoneal injection of endotoxin, the hepatic LDL-receptor expression and the plasma lipoprotein pattern were analyzed. Endotoxin increased plasma triglyceride and apoE in very low-density lipoproteins (VLDL) and intermediate-density lipoproteins, and decreased apoAI in high-density lipoproteins (HDL) in the endotoxin-sensitive mice (C3H/HeN), but not in the endotoxin-resistant mice (C3H/HeJ). These data indicate that a defective Lps gene impairs the endotoxin signaling to alter these lipoproteins. However, the hepatic LDL-receptor response to endotoxin in the endotoxin-resistant mice was similar to that in the endotoxin-sensitive mice. Thus, at a dose of 5 microg/mouse, endotoxin reduced hepatic LDL-receptor expression by 35% in C3H/HeN mice and by 52% in C3H/HeJ mice. At a dose of 50 microg/mouse, endotoxin reduced hepatic LDL-receptor expression by 61% in C3H/HeN mice and by 63% in C3H/HeJ mice. It is concluded that endotoxin suppresses hepatic LDL-receptor expression in vivo via a pathway independent of the Toll-like receptor 4.
Liao
W
W
Metabolism Unit, Center for Endocrinology and Metabolism, Department of Medicine, Karolinska Institute at Huddinge University Hospital, Huddinge, Sweden. wliao@bcm.tmc.edu
Rudling
M
M
Angelin
B
B
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D029721:Drosophila Proteins; D004731:Endotoxins / Q000633:toxicity*; D004926:Escherichia coli; D005786:Gene Expression Regulation / Q000187:drug effects*; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000502:physiology*; D011973:Receptors, LDL / Q000235:genetics*; D013045:Species Specificity; D051193:Toll-Like Receptors; D014158:Transcription, Genetic / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
D029721:Drosophila Proteins; D004731:Endotoxins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D051193:Toll-Like Receptors; D014280:Triglycerides; D002784:Cholesterol