PCSK9 in critical illness – It’s not all about lipids

Proprotein Convertase Subtilisin-Kexin type 9 (PCSK9) is a key regulator of lipid metabolism, binding to the low-density lipoprotein receptor (LDLR) on the cell surface and preventing its recycling, thereby reducing clearance of LDL cholesterol (LDLc) from the circulation. For this reason, it constitutes an alternative therapeutic target for the control of hypercholesterolaemia, with the development of monoclonal antibodies against PCSK9 occurring within 12 years of the protein's discovery. Recent research has also suggested an inflammatory role played by PCSK9, with elevated plasma levels identified in critical illnesses such as sepsis and Acute Respiratory Distress Syndrome, where PCSK9 is thought to reduce bacterial endotoxin clearance and may exacerbate inflammation. Further work is required in order to clarify the exact role played by PCSK9 in extra-hepatic tissues, and the potential benefits of its pharmacological inhibition.