Role of lipoproteins and proprotein convertase subtilisin/kexin type 9 in endotoxin clearance in sepsis.

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a recent high-impact cardiovascular intervention aimed at reducing low-density lipoprotein (LDL) cholesterol levels. Notably, pathogen lipids are also carried in lipoprotein particles and are cleared by hepatocyte LDL receptors. Therefore, the role of PCSK9 in sepsis is reviewed. Endogenous PCSK9 decreases clearance of LDL cholesterol by decreasing the number of LDL receptors on hepatocytes. Similarly, PCSK9 decreases clearance of pathogen lipids, such as endotoxin, carried in LDL. Pathogen lipids, such as lipopolysaccharide (LPS) from gram-negative organisms or lipoteichoic acid from gram-positive organisms, are carried in high-density lipoprotein, LDL, and very low-density lipoprotein particles. Transfer proteins that handle pathogen lipids (e.g., LPS binding protein) are homologous to transfer proteins that handle cholesterol (e.g., phospholipid transfer protein, cholesterol ester transfer protein). Reduction in PCSK9 function results in increased LPS clearance, a decreased inflammatory response, and improved clinical outcomes in mice. PCSK9 inhibition improves survival in septic mice. Similarly, humans who carry loss-of-function variants of the PCSK9 gene have increased survival in sepsis. PCSK9 inhibition may be a useful strategy to increase pathogen lipid clearance in the treatment of patients with sepsis.