Journal
CURRENT OPINION IN LIPIDOLOGY
Volume 25, Issue 5, Pages 387-393Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/MOL.0000000000000114
Keywords
hepatocyte nuclear factor 1 alpha; low-density lipoprotein-cholesterol; low-density lipoprotein receptor; proprotein convertase subtilisin/kexin type-9; reverse cholesterol transport
Funding
- Canadian Institutes of Health Research [MOP 106462]
- Heart and Stroke Foundation of Canada
- Heart and Stroke Foundation of Canada New Investigator Award
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Purpose of review Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to LDL receptor (LDLR) and targets it for lysosomal degradation in cells. Decreased hepatic clearance of plasma LDL-cholesterol is the primary gauge of PCSK9 activity in humans; however, PCSK9's evolutionary role may extend to other lipoprotein classes and processes. This review highlights studies that are providing novel insights into physiological regulation of PCSK9 transcription and plasma PCSK9 activity. Recent findings Recent studies indicate that circulating PCSK9 binds to apolipoprotein B100 on LDL particles, which in turn inhibits PCSK9's ability to bind to cell surface LDLRs. Negative feedback of secreted PCSK9 activity by LDL could serve to increase plasma excursion of triglyceride-rich lipoproteins and monitor lipoprotein remodeling. Recent findings have identified hepatocyte nuclear factor-1 alpha as a key transcriptional regulator that cooperates with sterol regulatory element-binding protein-2 to control PCSK9 expression in hepatocytes in response to nutritional and hormonal inputs, as well as acute inflammation. Summary PCSK9 is an established target for cholesterol-lowering therapies. Further study of PCSK9 regulatory mechanisms may identify additional control points for pharmacological inhibition of PCSK9-mediated LDLR degradation. PCSK9 function could reflect ancient roles in the fasting-feeding cycle and in linking lipoprotein metabolism with innate immunity.
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