PCSK9
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Location (UCSC) | Chr 1: 55.04 – 55.06 Mb | Chr 4: 106.3 – 106.32 Mb | |||||||
PubMed search | [3] | [4] |
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an
PCSK9 is ubiquitously expressed in many tissues and cell types.
PCSK9 has medical importance because it acts in lipoprotein homeostasis. Agents that block PCSK9 can lower LDL particle concentrations. The first two PCSK9 inhibitors, alirocumab and evolocumab, were approved as once every two week injections, by the U.S. Food and Drug Administration in 2015 for lowering LDL-particle concentrations when statins and other drugs were not sufficiently effective or poorly tolerated. The cost of these new medications, as of 2015[update], was $14,000 per year at full retail; judged of unclear cost effectiveness by some.[14] While these medications are prescribed by many physicians, the payment for prescriptions are often denied by insurance providers.[15][16][17] As a result, pharmaceutical manufacturers lowered the prices of these drugs.[18]
History
In February 2003,
In July 2015, the FDA approved the first PCSK9 Inhibitor drugs for medical use.[24]
Structure
Gene
The PCSK9 gene resides on chromosome 1 at the band 1p32.3
Protein
PCSK9 is a member of the
The solved structure of PCSK9 reveals four major components in the pre-processed protein: the
Function
Synthesis
PCSK9 is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum.[7] It is expressed mainly in liver, intestine, kidney, skin and the central nervous system.[34] After being processed in the ER, PCSK9 co-localizes with the protein sortilin on its way through the Golgi and trans-Golgi complex. A PCSK9-sortilin interaction is proposed to be required for cellular secretion of PCSK9.[35] In healthy humans, plasma PCSK9 levels directly correlate with plasma sortilin levels, following a diurnal rhythm similar to cholesterol synthesis.[36][37] The plasma PCSK9 concentration is higher in women compared to men, and the PCSK9 concentrations decrease with age in men but increase in women, suggesting that estrogen level most likely plays a role.[38][39] PCSK9 gene expression can be regulated by sterol-response element binding proteins (SREBP-1/2), which also controls LDLR expression.[36]
Cholesterol homeostasis
As a negative post-translational regulator of the low-density lipoprotein receptor (LDLR), PCSK9 plays a major role in cholesterol homeostasis. Upon binding of low-density lipoprotein (LDL) cholesterol to its receptor, the resulting LDLR-LDL complex is internalized. When exposed to the acidic environment within the resulting endosome LDLR adopts a hairpin conformation.[40] This conformational change in turn induces the dissociation of the LDL-LDLR complex, allowing LDLR to be recycled back to the plasma membrane. Binding of PCSK9 binds to cell surface LDLR (through the LDLR EGF-A domain) also induces LDLR internalization. However, unlike LDL binding, PCSK9 prevents LDLR from undergoing a conformational change. This inhibition redirects LDLR to a lysosome where it is degraded.[40] Thus, PCSK9 lowers cell surface expression of LDLR and thereby decreases metabolism of LDL-particles, which in turn may lead to hypercholesterolemia.[41] PCSK9 also plays an important role in triglyceride-rich apoB lipoprotein production in small intestine and postprandial lipemia.[42][43][44]
Skin and inflammation
ApoB lipoprotein, PCSK9, and the genes involved in cholesterol synthesis are highly expressed in the epidermis.[45][46] The cutaneous expression of PCSK9 is likely important for proper skin barrier formation as ceramides, free fatty acids, and cholesterol are the three major components of the epidermal lipid barrier.[47] Matching its function in cholesterol homeostasis, there is a gradient of PCSK9 expression in the epidermis. PCSK9 is selectively expressed in basal and spinous layer keratinocytes with little to no expression in granular layer keratinocytes.[45] In contrast to basal layer keratinocytes, granular layer keratinocytes release large amounts of cholesterol and other lipids to form a lipid rich "mortar" in the intracellular space between keratinocytes.[47] In addition to its likely role in epidermal lipid barrier formation, PCSK9 has also been linked to skin inflammation. For example, genetic variants of PCSK9 have been linked psoriasis,[45] and knockdown expression of PCSK9 in keratinocytes results in increase expression of IL-36G and other keratinocyte-derived inflammatory mediators.[45]
Other functions of PCSK9
PCSK9 may also have a role in the differentiation of cortical neurons.[5]
Clinical significance
Variants of PCSK9 can reduce or increase circulating cholesterol. LDL-particles are removed from the blood when they bind to LDLR on the surface of cells, including liver cells, and are taken inside the cells. When PCSK9 binds to an LDLR, the receptor is destroyed along with the LDL particle. PCSK9 degrades LDLR by preventing the hairpin conformational change of LDLR.[48] If PCSK9 does not bind, the receptor will return to the surface of the cell and can continue to remove LDL-particles from the bloodstream.[49]
Other variants are associated with a rare autosomal dominant familial hypercholesterolemia (HCHOLA3).[50][21][51] The mutations increase its protease activity, reducing LDLR levels and preventing the uptake of cholesterol into the cells.[21]
In humans, PCSK9 was initially discovered as a
As PCSK9 binds to LDLR, which prevents the removal of
In addition to its lipoprotein synthetic and pro-atherosclerotic effects, PCSK9 is involved in glucose metabolism and obesity,[66] regulation of re-absorption of sodium in the kidney which is relevant in hypertension.[67][68] Furthermore, PCSK9 may be involved in bacterial or viral infections and sepsis.[69][70][71] In the brain the role of PCSK9 is still controversial and may be either pro-apoptotic or protective in the development of the nervous system.[5] PCSK9 levels have been detected in the cerebrospinal fluid at a 50-60 times lower level than in serum.[72]
Clinical marker
A multi-locus genetic risk score study based on a combination of 27 loci including the PCSK9 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[8]
Inhibitors
Several studies have determined the potential use of PCSK9 inhibitors in the treatment of hyperlipoproteinemia (commonly called hypercholesterolemia).[14][53] Furthermore, loss-of-function mutations in the PCSK9 gene result in lower levels of LDL and protection against cardiovascular disease.[57]
PCSK9 inhibitor drugs are now approved by the FDA to treat familial hypercholesterolemia.[15]
As a drug target
Drugs can inhibit PCSK9, leading to lowered circulating LDL particle concentrations. Since LDL particle concentrations are thought by many experts to be a driver of
A review published in 2015 concluded that these agents, when used in patients with high LDL-particle concentrations (thus at greatly elevated risk for cardiovascular disease) seem to be safe and effective at reducing all-cause mortality, cardiovascular mortality, and heart attacks.[82] However a 2020 review concluded that while PCSK9 inhibitor treatment provides additional benefits beyond maximally tolerated statin therapy in high-risk individuals,[83] PCSK9 inhibitor use probably produces little or no difference in mortality.[84]
In a meta-analysis involving data from 3 randomized controlled trials, early initiation of PCSK9 inhibitors within 72 hours of acute coronary event along with high dose statin was associated with a more rapid decline in cholesterol levels 4 weeks after the cardiac event, which translated into a significant reduction hospital readmission post-acute cardiac event.[86]
Warning
An FDA warning in March 2014 about possible cognitive adverse effects of PCSK9 inhibition caused concern, as the FDA asked companies to include neurocognitive testing into their
Monoclonal antibodies
A number of
A possible side effect of the monoclonal antibody might be irritation at the injection site. Before the infusions, participants received oral corticosteroids, histamine receptor blockers, and acetaminophen to reduce the risk of infusion-related reactions, which by themselves will cause several side effects.[89]
Peptide mimics
Peptides that mimick the EGFA domain of the LDLR that binds to PCSK9 have been developed to inhibit PCSK9.[90]
Gene silencing
The PCSK9
In 2021, scientists demonstrated that
In 2023, a clinical trial demonstrated that
Vaccination
A vaccine that targets PCSK9 has been developed to treat high LDL-particle concentrations. The vaccine uses a VLP (
Naturally occurring inhibitors
The plant alkaloid berberine inhibits the transcription of the PCSK9 gene in immortalized human hepatocytes in vitro,[101] and lowers serum PCSK9 in mice and hamsters in vivo.[102] It has been speculated[102] that this action contributes to the ability of berberine to lower serum cholesterol.[103] Annexin A2, an endogenous protein, is a natural inhibitor of PCSK9 activity.[104]
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Further reading
- Abifadel M, Rabès JP, Boileau C, Varret M (June 2007). "[After the LDL receptor and apolipoprotein B, autosomal dominant hypercholesterolemia reveals its third protagonist: PCSK9]". Annales d'Endocrinologie (in French). 68 (2–3): 138–146. PMID 17391637.
- Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, et al. (November 2005). "Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia". Human Mutation. 26 (5): 497. S2CID 24247670.
- Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, et al. (November 2004). "NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol". The Journal of Biological Chemistry. 279 (47): 48865–48875. PMID 15358785.
- Lalanne F, Lambert G, Amar MJ, Chétiveaux M, Zaïr Y, Jarnoux AL, et al. (June 2005). "Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells". Journal of Lipid Research. 46 (6): 1312–1319. PMID 15741654.
- Lambert G (June 2007). "Unravelling the functional significance of PCSK9". Current Opinion in Lipidology. 18 (3): 304–309. S2CID 29895011.
- Leren TP (May 2004). "Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia". Clinical Genetics. 65 (5): 419–422. S2CID 27905111.
- Maxwell KN, Breslow JL (May 2004). "Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype". Proceedings of the National Academy of Sciences of the United States of America. 101 (18): 7100–7105. PMID 15118091.
- Maxwell KN, Soccio RE, Duncan EM, Sehayek E, Breslow JL (November 2003). "Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice". Journal of Lipid Research. 44 (11): 2109–2119. PMID 12897189.
- Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD, et al. (December 2005). "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response". Arteriosclerosis, Thrombosis, and Vascular Biology. 25 (12): 2654–2660. PMID 16224054.
- Naureckiene S, Ma L, Sreekumar K, Purandare U, Lo CF, Huang Y, et al. (December 2003). "Functional characterization of Narc 1, a novel proteinase related to proteinase K". Archives of Biochemistry and Biophysics. 420 (1): 55–67. PMID 14622975.
- Ouguerram K, Chetiveaux M, Zair Y, Costet P, Abifadel M, Varret M, et al. (August 2004). "Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9". Arteriosclerosis, Thrombosis, and Vascular Biology. 24 (8): 1448–1453. PMID 15166014.
- Pisciotta L, Priore Oliva C, Cefalù AB, Noto D, Bellocchio A, Fresa R, et al. (June 2006). "Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia". Atherosclerosis. 186 (2): 433–440. PMID 16183066.
- Shibata N, Ohnuma T, Higashi S, Higashi M, Usui C, Ohkubo T, et al. (December 2005). "No genetic association between PCSK9 polymorphisms and Alzheimer's disease and plasma cholesterol level in Japanese patients". Psychiatric Genetics. 15 (4): 239. PMID 16314752.
- Sun XM, Eden ER, Tosi I, Neuwirth CK, Wile D, Naoumova RP, Soutar AK (May 2005). "Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia". Human Molecular Genetics. 14 (9): 1161–1169. PMID 15772090.
- Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, et al. (March 2004). "A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree". Human Genetics. 114 (4): 349–353. S2CID 11884805.
- Varret M, Rabès JP, Saint-Jore B, Cenarro A, Marinoni JC, Civeira F, et al. (May 1999). "A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32". American Journal of Human Genetics. 64 (5): 1378–1387. PMID 10205269.