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 endoto xin in C3H/HeJ mice. Eighteen hours after an intraperitoneal injection of e ndotoxin, the hepatic LDL-receptor expression and the plasma lipoprotein pa ttern were analyzed, Endotoxin increased plasma triglyceride and apoE in ve ry low-density lipoproteins (VLDL) and intermediate-density lipoproteins, a nd decreased apoAI in high-density lipoproteins (HDL) in the endotoxin-sens itive mice (C3H/HeN), but not in the endotoxin-resistant mice (C3H/HeJ). Th ese 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 endot oxin-sensitive mice. Thus, at a dose of 5 mu g/mouse, endotoxin reduced hep atic LDL-receptor expression by 35% in C3H/HeN mice and by 52% in C3H/HeJ m ice, At a dose of 50 mu g/mouse, endotoxin reduced hepatic LDL-receptor exp ression 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 pat hway independent of the Toll-like receptor 4.