Endotoxin suppresses mouse hepatic low-density lipoprotein–receptor expression via a pathway independent of the toll-like receptor 4

✍ Scribed by Wei Liao; Mats Rudling; Bo Angelin

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 152 KB
• Volume: 30
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510300524

✦ Synopsis

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 g/mouse, endotoxin reduced hepatic LDLreceptor expression by 35% in C3H/HeN mice and by 52% in C3H/HeJ mice. At a dose of 50 g/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. (HEPATOLOGY 1999;30:1252-1256.)

Endotoxin is one of the most active bacterial products that mediate gram-negative bacterial septic shock. Endotoxin also profoundly alters the metabolism of plasma lipids and lipoproteins, leading to a hyperlipidemic state. 1,2 In endotoxintreated animals, plasma triglycerides, and to a lesser extent plasma cholesterol levels, are increased. The endotoxininduced hyperlipidemia is characterized by accumulation of lipids within very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL), whereas high-density lipoproteins (HDL) are decreased or unchanged. Both a reduced clearance of VLDL, caused by inhibition of lipoprotein lipase, and a stimulation of hepatic VLDL production contribute to the endotoxin-induced hypertriglyceridemia. This hyperlipidemic response of the infected host to endotoxin is generally regarded as a part of the host-defense mechanism. 3,4 Other mechanisms may also operate in the development of endotoxin-induced hyperlipidemia. Thus, in HepG2 cells endotoxin interferes with cellular LDL uptake by forming complexes with LDL. 5,6 Injection of endotoxin together with 125 I-LDL inhibits 125 I-LDL clearance in rats. 7 Recently, we have shown that endotoxin reduces rat hepatic LDL-receptor expression and increases circulating apoB-containing lipoproteins in vivo. 8 Endotoxin-induced inhibition of LDL-receptor expression is thus probably also involved in the pathogenesis of endotoxin-induced hyperlipidemia.

C3H/HeJ mice are resistant to endotoxin challenge. Along with C3H/HeN mice, C3H/HeJ mice are derived from their common progenitor strain, C3H/He. Neither C3H/He nor C3H/HeN mice have the endotoxin tolerance phenotype characteristic of C3H/HeJ. Genetic analysis has established that this phenotype is under the control of a single locus on mouse chromosome 4, named Lps. 9,10 The defective Lps gene confers C3H/HeJ mice on resistance to endotoxin challenge. Recent studies from three different groups have identified the Lps gene as encoding the Toll-like receptor 4. [11][12][13] In the current study, we used C3H/HeJ mice to investigate whether a defective Lps gene would impair the suppressive effect of endotoxin on hepatic LDL-receptor expression. As expected, endotoxin treatment was shown to induce hypertriglyceridemia in C3H/HeN mice, but not in C3H/HeJ mice. However, endotoxin was found to suppress hepatic LDLreceptor expression in both C3H/HeJ mice and C3H/HeN mice. Thus, endotoxin suppresses hepatic LDL-receptor expression in vivo via a pathway independent of the Toll-like receptor 4. Studies to show the relevance of this pathway in the control of hepatic LDL receptors, and thus plasma LDL cholesterol levels, will be of interest.

Methods

Animals and Experimental Procedure. Male C3H/HeN (endotoxinsensitive) and C3H/HeJ (endotoxin-resistant) mice were purchased from Bomholtgård A/S (Ry, Denmark). The animals (about 19 g, see