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Updated: Feb 28, 2026
A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice
Jean-Mathieu Berger1, Angel Loza Valdes1, Jesper Gromada2
1Departments of Internal Medicine and Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX.
Abstract:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that targets LDL receptors (LDLRs) for degradation in liver. Blocking the interaction of PCSK9 with the LDLR potently reduces plasma LDL cholesterol levels and cardiovascular events. Recently, it has been suggested that inhibition of PCSK9 might also improve outcomes in mice and humans with sepsis, possibly by increasing LDLR-mediated clearance of endotoxins. Sepsis is a complication of a severe microbial infection that has shared pathways with lipid metabolism. Here, we tested whether anti-PCSK9 antibodies prevent death from lipopolysaccharide (LPS)-induced endotoxemia. Mice were administered PCSK9 antibodies prior to, or shortly after, injecting LPS. In both scenarios, the administration of PCSK9 antibodies did not alter endotoxemia-induced mortality. Afterward, we determined whether the complete absence of PCSK9 improved endotoxemia-induced mortality in mice with the germ-line deletion of Pcsk9 Similarly, PCSK9 knockout mice were not protected from LPS-induced death. To determine whether low LDLR expression increased LPS-induced mortality, Ldlr mice and PCSK9 transgenic mice were studied after injection of LPS. Endotoxemia-induced mortality was not altered in either mouse model. In a human cohort, we observed no correlation between plasma inflammation markers with total cholesterol levels, LDL cholesterol, and PCSK9. Combined, our data demonstrate that PCSK9 inhibition provides no protection from LPS-induced mortality in mice.
Insights
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition does not protect against lipopolysaccharide-induced endotoxemia in mice. Studies showed no altered mortality in PCSK9 antibody-treated or knockout mice, nor in low LDL receptor models.
Area of Science:
- Biochemistry
- Immunology
- Cardiovascular Science
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets LDL receptors (LDLRs) for degradation, and its inhibition lowers LDL cholesterol.
- Emerging evidence suggested PCSK9 inhibition might benefit sepsis patients by enhancing LDLR-mediated endotoxin clearance.
- Sepsis involves severe microbial infections with pathways overlapping lipid metabolism.
Purpose of the Study:
- To investigate if anti-PCSK9 antibodies protect against lipopolysaccharide (LPS)-induced endotoxemia mortality in mice.
- To determine if the absence of PCSK9 or altered LDLR expression impacts endotoxemia survival.
Main Methods:
- Mice received PCSK9 antibodies before or after LPS injection.
- Mortality was assessed in PCSK9 knockout mice and LDLR knockout mice after LPS challenge.
- A human cohort was analyzed for correlations between inflammation markers, cholesterol levels, and PCSK9.
Main Results:
- PCSK9 antibody administration did not alter mortality in LPS-induced endotoxemia.
- PCSK9 knockout mice and mice with altered LDLR expression showed no protection against LPS-induced death.
- No correlation was found between plasma inflammation markers and lipid/PCSK9 levels in humans.
Conclusions:
- PCSK9 inhibition does not offer protection against LPS-induced endotoxemia mortality in mice.
- The LDLR-mediated clearance of endotoxins by PCSK9 is not a significant factor in endotoxemia survival in this model.
- These findings suggest PCSK9 inhibition is unlikely to be beneficial for sepsis treatment via endotoxin clearance.
