Reduced Proprotein convertase subtilisin/kexin 9 (PCSK9) function increases lipoteichoic acid clearance and improves outcomes in Gram positive septic shock patients

Abstract

Previous studies have shown lipopolysaccharide from Gram-negative bacteria is cleared from the circulation via LDL receptors on hepatocytes, which are downregulated by PCSK9. Whether clearance of Gram positive bacterial lipoteichoic acid (LTA) shows similar dependence on PCSK9, and whether this is clinically relevant in Gram positive human sepsis, is unknown. We examined survival data from three cohorts of patients who had Gram positive septic shock (n = 170, n = 130, and n = 59) and found that patients who carried a PCSK9 loss-of-function (LOF) allele had significantly higher 28-day survival (73.8%) than those with no LOF alleles (52.8%) (p = 0.000038). Plasma clearance of LTA was also found to be increased in PCSK9 knockout mice compared to wildtype control mice (p = 0.002). In addition, hepatocytes pre-treated with recombinant wildtype PCSK9 showed a dose-dependent decrease in uptake of fluorescently-labeled LTA (p < 0.01). In comparison to wildtype PCSK9, hepatocytes pre-treated with 3 different LOF variants of recombinant PCSK9 showed an increase in LTA uptake. This study shows the clearance of LTA follows a similar route as lipopolysaccharide, which is dependent on hepatic LDL receptors. This has important implications in health as strategies aimed at inhibiting PCSK9 function may be an effective treatment option for both Gram-positive and negative sepsis.

Relationship of Zonulin with Serum PCSK9 Levels after a High Fat Load in a Population of Obese Subjects

“…Despite the fact that the relationship between PCSK9 and intestinal permeability has not been studied in depth, it is known that LDL-R is implicated in LPS clearance [11]. Moreover, previous studies have shown that the inhibition of PCSK9 and the consequent promotion of LDL-R favor LPS detoxification [27][28][29], indicating PCSK9 as a possible regulator of LPS clearance. Therefore, PCSK9 reduction after fat load could help in the clearance of higher plasma concentrations of LPS resulting from the increased intestinal permeability due to high fat consumption in obese individuals.…”

Association of Serum PCSK9 Levels with Antibiotic Resistance and Severity of Disease in Patients with Bacterial Infections Admitted to Intensive Care Units

“…Some authors have shown that plasma PCSK9 levels are elevated equally in patients with gram-positive or gram-negative bacterial infections but that particularly high levels are seen in patients with Streptococcus pneumoniae bacteremia; further, a reduced plasma PCSK9 response in patients with bacteremia is associated with increased mortality [29]. The results of some studies have indicated that inhibiting PCSK9 function may be an effective treatment option for both gram-positive and gram-negative sepsis [30]. According to our results, despite all these quite convincing data indicating that serious infections and sepsis might be associated with elevated plasma PCSK9 levels, it seems that there is no association between PCSK9 levels and resistance to antibiotics or the condition of patients hospitalized in intensive care units.…”

PCSK9: A Potential Therapeutic Target for Sepsis

“…Moreover, PCSK9 KO mice showed improved serum lipoteichoic acid clearance compared to that of the wild type. Exactly, HepG2 hepatocytes pretreated with wild-type PCSK9 showed obvious decline in the lipoteichoic acid uptake than those with LOF variants of recombinant PCSK9 [ 26 ]. Nevertheless, there are still controversies on the roles of PCSK9 in the pathogenesis of sepsis.…”