The Central Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Septic Pathogen Lipid Transport and Clearance

Abstract

Microbial cell walls contain pathogenic lipids, including LPS in gram-negative bacteria, lipoteichoic acid in gram-positive bacteria, and phospholipomannan in fungi. These pathogen lipids are major ligands for innate immune receptors and figure prominently in triggering the septic inflammatory response. Alternatively, pathogen lipids can be cleared and inactivated, thus limiting the inflammatory response. Accordingly, biological mechanisms for sequestering and clearing pathogen lipids from the circulation have evolved. Pathogen lipids released into the circulation are initially bound by transfer proteins, notably LPS binding protein and phospholipid transfer protein, and incorporated into high-density lipoprotein particles. Next, LPS binding protein, phospholipid transfer protein, and other transfer proteins transfer these lipids to ApoB-containing lipoproteins, including low-density (LDL) and very-low-density lipoproteins and chylomicrons. Pathogen lipids within these lipoproteins and their remnants are then cleared from the circulation by the liver. Hepatic clearance involves the LDL receptor (LDLR) and possibly other receptors. Once absorbed by the liver, these lipids are then excreted in the bile. Recent evidence suggests pathogen lipid clearance can be modulated. Importantly, reduced proprotein convertase subtilisin/kexin type 9 activity increases recycling of the LDLR and thereby increases LDLR on the surface of hepatocytes, which increases clearance by the liver of pathogen lipids transported in LDL. Increased pathogen lipid clearance, which can be achieved by inhibiting proprotein convertase subtilisin/kexin type 9, may decrease the systemic inflammatory response to sepsis and improve clinical outcomes.

Update of Sepsis in the Intensive Care Unit

“…Pathogen lipids are carried within lipoprotein particles (high-density lipoprotein [HDL], very low-density lipoprotein and LDL-cholesterol) and transferred between these fractions especially from HDL to LDL. Transfer proteins such as phospholipid transfer protein and lipopolysaccharide binding protein guide this process [102] . PCSK9 increases LDL receptor activity by hepatocyte lysosomal degradation and thus decreases pathogen lipid clearance [102] .…”

The Understanding and Management of Organism Toxicity in Septic Shock

“…Hepatic clearance of LPS involves primarily the LDL receptor (LDLR) and possibly other receptors such as scavenger receptor class B type 1 (SRB1). After uptake by hepatocytes, PLs, mostly within LDL particles, are then excreted into the bile [22]. Recent evidence suggests that PL clearance can be modulated and that proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key players in this process.…”

“…PCSK9 targets the LDLR on hepatocytes for lysosomal degradation within cells, preventing LDLR recycling, and thereby decreasing LDLR concentrations and also the clearance of LPS. PCSK9 is thus a “bad guy.” In contrast, reduced PCSK9 activity increases LDLR concentration on the surface of hepatocytes and also the clearance of PLs transported in LDL by the liver [22]. Accordingly (discussed below in detail), PCSK9 inhibition may be a novel strategy to increase PL clearance and thus complement the established efficacy of early antibiotics in sepsis.…”

“…(3) Anti-PCSK9 therapy (MAb) binds to PCSK9 and inhibits PCSK9-induced degradation of LDLR, upregulating the hepatic clearance of LPS carried within LDL. Adapted from [22]. LPS, lipopolysaccharide; LDL, low-density lipoprotein; LDLR, LDL receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; Ab, monoclonal antibody.…”

The role of genetics and antibodies in sepsis

“…Figure 2 depicts immunoglobulin G and its major structural and functional components. Table 2 outlines the favorable characteristics and potential limitations of mAbs as therapeutic agents to treat infectious diseases (47)(48)(49)(50)(51)(52). Additionally, the costs for developing therapeutic mAbs have previously been thought to be cost prohibitive for clinical use.…”