Inflammation stimulates the expression of PCSK9

Abstract

Inflammation induces marked changes in lipid and lipoprotein metabolism. Proprotein convertase subtilisin kexin 9 (PCSK9) plays an important role in regulating LDL receptor degradation. Here, we demonstrate that LPS decreases hepatic LDL receptor protein but at the same time hepatic LDL receptor mRNA levels are not decreased. We therefore explored the effect of LPS on PCSK9 expression. LPS results in a marked increase in hepatic PCSK9 mRNA levels (4h 2.5-fold increase; 38h 12.5-fold increase). The increase in PCSK9 is a sensitive response with 1microg LPS inducing a (1/2) maximal response. LPS also increased PCSK9 expression in the kidney. Finally, zymosan and turpentine, other treatments that induce inflammation, also stimulated hepatic expression of PCSK9. Thus, inflammation stimulates PCSK9 expression leading to increased LDL receptor degradation and decreasing LDL receptors thereby increasing serum LDL, which could have beneficial effects on host defense.

Fig. 1. Effect of LPS administration on the expression of the LDL receptor in mouse liver

Mice were injected intraperitoneally with LPS (5mg/kg body weight). The animals were euthanized at the indicated times after LPS administration. Liver membranes and Western blots were carried out as described in the Materials and Methods section. Total RNA was isolated from liver tissue, cDNA was synthesized with reverse transcriptase, and quantitative real-time PCR performed as described in Materials and Methods section. A. LDL receptor protein levels at 16 and 38 hours post LPS administration. B. LDL receptor mRNA levels at various times after LPS administration. The data are presented as the mean +/− SEM. Data are expressed as a percentage of controls. N=4–5 per group. * p< 0.01, *** p< 0.001

Fig. 2. Effect of LPS administration on the expression of PCSK9 in mouse liver

Total RNA was isolated from liver tissue, cDNA was synthesized with reverse transcriptase, and quantitative real-time PCR performed as described in Materials and Methods section. A. Time course. Mice were injected intraperitoneally with LPS (5mg/kg body weight) and the animals were euthanized at the indicated times after LPS administration. B. Dose Response. Mice were injected intraperitoneally with the indicated dose of LPS and the animals were euthanized 16 hours after LPS administration. The data are presented as the mean +/− SEM. Data are expressed as a percentage of controls. N=4–5 per group. ** p< 0.005, *** p< 0.001

Fig. 3. Effect of zymosan and turpentine treatment on the expression of PCSK9 in mouse liver

Mice were injected intraperitoneally with zymosan (80mg/kg body weight) or subcutaneously with turpentine (100ul) and euthanized 16 hours after treatment. Total RNA was isolated from liver tissue, cDNA was synthesized with reverse transcriptase, and quantitative real-time PCR performed as described in Materials and Methods section. The data are presented as the mean +/− SEM. Data are expressed as a percentage of controls. N=4–5 per group. *** p< 0.001 vs. control.