The PCSK9 decade

Abstract

Abbreviations: ARH, autosomal recessive hypercholesterolemia; ASO, antisense oligonucleotide; CAD, coronary artery disease; CVD, cardiovascular disease; EGFA, epidermal growth factor-like repeat homology domain; FH, familial hypercholesterolemia; HDL-C, highdensity lipoprotein cholesterol; HNF1a, hepatocyte nuclear factor 1a; LDL-C, low-density lipoprotein cholesterol; LDLR, LDL receptor; LNA, locked nucleic acid; LOD, logarithm of the odds; monoclonal antibody, MAb; PCSK9, proprotein convertase subtilisin kexin type 9; siRNA, small interfering RNA; SREBP2, sterol-responsive element-binding protein 2.

Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases

“…In addition, a recent study documented a function for sortilin in promoting the release of PCSK9 from the liver 43 . PCSK9 binds to the LDL receptor and causes its lysosomal degradation, either in the biosynthetic pathway of the cell or following secretion of the protease into the extracellular space (reviewed in 44 ). Hepatocytes are the main source of circulating PCSK9 and high plasma levels of the protease correlate with low LDL receptor activity (and hence higher LDL concentrations).…”

FoxO3 Transcription Factor and Sirt6 Deacetylase Regulate Low Density Lipoprotein (LDL)-cholesterol Homeostasis via Control of the Proprotein Convertase Subtilisin/Kexin Type 9 (Pcsk9) Gene Expression

“…Now we know that PCSK9 is expressed mainly in the liver as a ϳ72-kDa precursor and can be auto-cleaved in the endoplasmic reticulum to an ϳ62-kDa mature form that is secreted to plasma. Circulating PCSK9 binds to the extracellular EGF-A domain of the LDLR and targets it for degradation in the lysosome (5). The physiological function of PCSK9 in the control of LDL-cholesterol has also been confirmed by mouse genetics.…”

“…Since the discovery of PCSK9 mutations in the autosomal dominant hypercholesterolemia patients a decade ago (4), significant progress has been made in the understanding of PCSK9 biochemistry and pathophysiology (5). Now we know that PCSK9 is expressed mainly in the liver as a ϳ72-kDa precursor and can be auto-cleaved in the endoplasmic reticulum to an ϳ62-kDa mature form that is secreted to plasma.…”

PCSK9 inhibitors for LDL lowering

“…Statins deplete intracellular cholesterol and upregulate LDL receptor transcription through sterol regulatory element-binding protein-2 (SREBP-2) (9). As PCSK9 transcription is also regulated by SREBP-2, PCSK9 levels are increased with statin therapy, which attenuates statins' LDL-C lowering effects (9). Consistent with this, PCSK9 knockout mice exhibit an exaggerated LDL-C response to statin treatment (10).…”