Inflammation stimulates the expression of PCSK9

doi:10.1016/j.bbrc.2008.07.023

Biochemical and Biophysical Research Communications

Volume 374, Issue 2, 19 September 2008, Pages 341-344

https://doi.org/10.1016/j.bbrc.2008.07.023 Get rights and content

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 (4 h 2.5-fold increase; 38 h 12.5-fold increase). The increase in PCSK9 is a sensitive response with 1 μg LPS inducing a ½ 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.

Section snippets

Materials and methods

Materials. LPS (Escherichia coli 55:B5) was obtained from Difco Laboratories and diluted in pyrogen-free 0.9% saline. Zymosan A and TRI Reagent were purchased from Sigma (St. Louis, MO). Oil of turpentine was purchased from BDH Laboratory Supplies (Poole, England). LightCycler^® 450 SYBR Green I Master was purchased from Roche Applied Science (Indianapolis, IN), and iScript cDNA Synthesis Kit from BIO-RAD (Hercules, CA).

Animals. Female C57BL/6 mice (8 weeks old) were obtained from Charles River

Results and discussion

Our initial experiments determined the effect of the administration of LPS, a TLR 4 activator, on hepatic LDL receptor protein levels. As reported by other investigators, LPS treatment resulted in a marked decrease in LDL receptor protein levels in the liver (∼60% decrease) (Fig. 1A) [2], [3]. Fig. 1B shows the effect of LPS on hepatic LDL receptor mRNA levels. As reported by other investigators [3], we also observed an early decrease in LDL receptor mRNA levels (50% decrease at 4 and 8 h) but

Acknowledgments

This work was supported by grants from the Research Service of the Department of Veterans Affairs and by National Institutes of Health Grant 5 RO1 AR049932.

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Citation Excerpt :
The expression pattern of PCSK9 in mammals has been associated with Sterol Regulatory Element binding protein-2 (SREBP-2) [27]; up-regulated PCSK9 can decrease in hepatic LDL receptors and an increase in serum LDL [20]. During the stimulation of zymosan (a fungal product that activates TLR2) or adenovirus, the expression is significant increase, leading to increase the degradation of LDL receptor, and increase serum LDL level [20,24]. In this study, PCSK9 mRNA was significantly upregulated response to SGIV infection.
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in mammals is a multifunctional protein. In this study, PCSK9 of marine fish Epinephelus coioides was characterized. The full-length cDNA of E. coioides PCSK9 was 2458 bp in length containing 185 bp 5′ UTR, 263 bp 3′ UTR and 2010 bp open reading frame (ORF) encoding 669 amino acids with the predicted molecular weight of 71 kDa and the theoretical PI of 6.6. Similar to other members of PCSK9 family, E. coioides PCSK9 has three conserved domains: Inhibitor_ I9 super family, Peptidases_ S8_ PCSK9_ Proteinase K_ like, and PCSK9_ C-CRD super family. E. coioides PCSK9 mRNA could be detected in all the tissues examined by real-time quantitative PCR, with the highest expression in the brain, followed by skin, trunk kidney, head kidney, intestine, blood, liver, spleen, gill, muscle and heart. E. coioides PCSK9 was distributed in both the cytoplasm and nucleus. The expression of E. coioides PCSK9 was significantly upregulated during Singapore grouper iridovirus (SGIV) infection. Upregulated PCSK9 could significantly affect the activities of nuclear factor kappaB (NF-κB) promoter, SGIV-induced apoptosis, and the expressions of the key SGIV genes (ICP18, LITAT, MCP, and VP19) and the E. coioides proinflammatory factors (IL-6, IL-1β, IL-8, and TNF-α). The results illustrated that E. coioides PCSK9 might be involved in the pathogen infection by regulating the innate immune response.

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Inflammation stimulates the expression of PCSK9

Abstract

Section snippets

Materials and methods

Results and discussion

Acknowledgments

J. Lipid Res.

J. Lipid Res.

Trends Biochem. Sci.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Lipid Res.

J. Biol. Chem.

J. Lipid Res.

J. Lipid Res.

J. Lipid Res.

J. Biol. Chem.

J. Biol. Chem.

J. Lipid Res.