The role of lipids and PCSK9 in long-term outcomes of sepsis

Lipids are important players in the host response to sepsis. High-density lipoprotein (HDL) binds avidly to pathogen lipids, such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA), neutralizing their inflammatory effects. Pathogen lipids within HDL are transferred to low-density lipoprotein (LDL) and cleared from the circulation by the liver in a process mediated by the LDL receptor (LDLR). In recent decades, more patients are surviving sepsis and being discharged from hospital. Studies analyzing long-term outcomes of sepsis have demonstrated a greater risk of late death, re-infection(s), late organ dysfunction(s), and re-hospitalization(s) in sepsis survivors compared to subjects never exposed to sepsis. Inadequate clearance of pathogens at the acute phase of sepsis and persistent immune dysfunction are possible factors associated with increased risk of adverse long-term outcomes in sepsis survivors. In this work, we hypothesized that plasma HDL-cholesterol levels are positively associated with decreased risk of sepsis-associated acute kidney injury (AKI), late kidney impairment or death, and that genetic variants in genes known to regulate HDL-C would impact the risk of AKI during sepsis. Finally, the role of proprotein convertase subtilisin-kexin type 9 (PCSK9),a major regulator of LDL plasma levels and LDL receptor metabolism in the long-term outcomes of sepsis was evaluated through: i) analysis of the impact of PCSK9 loss-of-function genotype in a composite outcome composed by 1-year death or infection-related readmission (IRR), and ii) analysis of the effects of PCSK9 inhibitors on the long-term inflammation in mouse model of sepsis. This study demonstrated that low plasma levels of HDL-C measured at sepsis admission increased significantly the risk of AKI, kidney dysfunction and/or long-term death. Moreover, the HDL-related cholesteryl ester transfer protein (CETP) variant rs1800777 (allele A) was strongly associated with low levels of HDL-C and increased risk of AKI during sepsis. Last, we observed that the presence of multiple PCSK9 loss-of-function alleles decreased the risk of the death or IRR in sepsis-survivors.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat