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Facts about Proprotein convertase subtilisin/kexin type 9.
Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May stop the recycling of LDLR from endosomes to the cell surface or guide it to lysosomes for degradation.
Mouse | |
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Gene Name: | Pcsk9 |
Uniprot: | Q80W65 |
Entrez: | 100102 |
Belongs to: |
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peptidase S8 family |
EC 3.4.21; EC 3.4.21.111; FH3; FH3neural apoptosis regulated convertase 1; FHCL3; HCHOLA3; hypercholesterolemia, autosomal dominant 3; LDLCQ1; NARC1; NARC-1; NARC-1convertase subtilisin/kexin type 9 preproprotein; NARC1EC 3.4.21.-; Neural apoptosis-regulated convertase 1; PC9; PCSK9; Proprotein Convertase 9; proprotein convertase subtilisin/kexin type 9; Subtilisin/kexin-like protease PC9
Mass (kDA):
74.823 kDA
Mouse | |
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Location: | 4|4 C7 |
Sequence: | 4; |
Hepatocytes, kidney mesenchymal cells, intestinal ileum, colon epithelia and embryonic brain telencephalon neurons.
This article will discuss how the PCSK9 marker could aid in the field of research. Boster scientists can submit results for species, applications, or special samples to earn product credits. This marker has many advantages available to scientists across the world. Read on to learn more. Below are a few of most significant uses for the PCSK9 markers in the scientific community. Many scientists are interested in the potential of the PCSK9 marker to be used in clinical applications.
Sepsis is characterized by inflammation and lipid absorption. PCSK9 overexpression is a major reason for this. Human liver cells have the capacity to express PCSK9, but its overexpression causes organ dysfunctions. PCSK9 also enhances the toll-like receptor function of macrophages. Its function in sepsis isn't yet understood.
In vivo, PCSK9 is essential for the lipid clearance of pathogens. Patients with sepsis who do not have it could be more likely to survive. In addition, the overexpression of PCSK9 can cause a rise in multiorgan pathology of bacterial. In this study, patients deficient in PCSK9 had a better chance of survival than those with normal levels of PCSK9 expression.
The expression of inflammatory and immune gene products was assessed by RNA extraction using the QIAGEN RNeasy kit. In the presence or absence of PCSK9 supplementation, levels of RNA were assessed in primary monocytes as well as monocyte-derived dendritic cell populations. We identified seven genes that were marginally enhanced by PCSK9 expression using NanoString nCounter. We also examined 23 genes that were either downregulated or upregulated by PCSK9. These genes included the gene that codes for NFKB which regulates TNF production, and SREBP2.
Interestingly, It is interesting that the PCSK9 protein was not associated with severity of the disease or the resistance of patients to antibiotics. In a case study, a PCSK9 inhibitor was used in a Mexican boy who had compound heterozygous familial hypercholesterolemia. Another study was published in J. Endocr. Soc. There was no evidence that suggested that there is a causal link between PCSK9 expression and early sepsis.
This gene is part of the PCSK family of proprotein convertases. This group is involved with numerous inflammation-related processes. It is named after its structural similarity with subtilisin. The position 32.3 of the short arm of chromosome 1, is where you will find the PCSK9 gene. It has three domains, 12 exons and 11 introns. Multiple functions of regulation are performed by the genes that encode PCSK9.
Another study investigated the role of PCSK9 and AdipoR in the development of psoriasis. In a case study researchers discovered that PCSK9 expression in mice was linked to an elevated level of NAFLD (non-alcoholic fatty liver disease). Patients suffering from NAFLD, which is a metabolic disorder, saw their PCSK9 levels increase. The researchers of the study also found a link between PCSK9 levels and the accumulation of liver fat.
The PCSK9 protein that is found in plasma, regulates cholesterol homeostasis by interfacing with LDLR (low-density lipoprotein receptors) and LDLRAP1 (very low-density lipoprotein receptor). These proteins are involved in the degrading of LDL through a process known as the ubiquitination. In addition to binding to LDLR PCSK9 is also involved in the degradation of LDLR and its clearance from plasma.
In addition the elevated levels of PCSK9 have been associated with atrial fibrillation. These conditions could be related to an increase in platelet activation. Furthermore, PCSK9 expression has been found to be positively related to urinary 11-dehydrothromboxane B2 excretion, which is a marker of atherosclerosis progression. These findings suggest that PCSK9 could be involved in the regulation of cholesterol homeostasis through targeting platelet function.
PCSK9's activity regulates the degradation of LDL-C by directing it towards lysosomes. This happens by binding LDLR to the PCSK9 catalyst domain. LDLR is then transported to the endosomes through endocytosis. There, it is degraded. PCSK9 is also responsible for the degradation o LDLR through its interaction with it, resulting in higher levels of LDL (a) and Lp(a) and Lp(a), respectively.
Molecular pathways implicated in PCSK9 regulate a variety of other proteins in the cell. PCSK9 transcription is inhibited in a variety of cell types by inhibiting the mTORC1 function. The inhibition of HNF1a activity does no affect PCSK9 expression in tumor-suppressor cells. However the inhibition of HNF1a activity does not affect the function of SREBP2 within human cells.
A multiethnic investigation of PCSK9 function in Dallas County, USA, identified a common ancestor of animals and humans. African Americans with the PCSK9 mutation had 40 percent lower levels of LDL C than those who did not have the gene. The results suggested that PCSK9 interaction with LDLR receptors might not cause the degrading of LDL-C.
PCSK9 is a member of the serine protease familia and is closely related with subtilisin from bacterial species. Other serine proteases include proprotein convertase 1 furin, and paired amino acids cleaving enzyme 4. PC7 and PC1. These proteins exert unique physiological roles. The activity of PCSK9 is essential to mature and is essential to maintaining lipid and cholesterol homeostasis.
In addition to regulating lipid homeostasis and immune responses, PCSK9 regulates these processes. There are many processes involved in PCSK9 regulation. These include the expression of genes that code for PCSK9.
Cross-talk is a result of two important signaling pathways. LXRs and SREBPs regulate the expression of RNF145, and activation of LXRs results in transduction of RNF145. The function of RNF145 can be increased, resulting in lower the levels of cholesterol in the plasma. However, the acute suppression of PCSK9 could block the expression of genes that are involved in cholesterol biosynthesis.
There are a variety of clinical applications for PCSK9. It has been discovered to be linked with CVMMs, LDL-C, non HDL-C, and HbA1C. Recent research has revealed that elevated PCSK9 levels were the most reliable predictors of adverse cardiovascular outcomes for diabetic patients with stable CAD. These findings suggest that elevated PCSK9 levels and DM may be combined to enhance our ability to predict cardiovascular events.
The role of the PCSK9 protein in the formation of plaques is unclear, but it does regulate the LDLR levels in the liver. Despite this uncertainty, some researchers have begun studying the relationship between PCSK9 levels and subclinical atherosclerosis. One study conducted by Chan et al.84 studied the plasma PCSK9 levels in 295 patients who were asymptomatic and observed a significant correlation between high PCSK9 concentration and carotid wall thickness.
The PCSK9 gene codes for instructions for the production of an enzyme that binds to the receptors of low density lipoproteins. These receptors play a crucial role in regulating cholesterol levels in the blood. Although the receptors can be found in various tissues, they are most abundant in the liver. This eliminates the majority of excess cholesterol. While the discovery of PCSK9 is exciting but its clinical applications are not as extensive.
PCSK9 is an inflammatory protein that interacts with liver proteins as well as extrahepatic tissue. It also interacts with other members of the LDLR family, which results in degradation or downstream signaling. There are many questions that remain unanswered concerning the clinical applications of PCSK9 in patients suffering from various diseases. The next step is to examine PCSK9 levels in patients with advanced hepatic disease.
A significant number of patients developed MI after receiving PCSK9 inhibitor therapy. Patients in the most high PCSK9 QV had a significantly higher rate of MI than those in the lowest. It also indicated a trend that PCSK9 levels were associated with a higher risk of ischemic stroke in patients suffering from DM. Thus, clinical applications for PCSK9 markers are growing in the medical field.
These studies show that PCSK9 levels are a reliable predictor of atherosclerosis. However their clinical relevance is not known. The SURDIAGENE study, which comprised 716 women who were initially healthy and found a similar result for DM patients. However, more research is needed in order to determine the clinical utility and clinical value of PCSK9 in CAD patients. These studies are encouraging and suggest that PCSK9 measurement could be an alternative for patients suffering from CAD.
Researchers discovered that therapeutic RNAi targeting PCSK9 reduced cholesterol levels in plasma in rodents and nonhuman primates. This finding was consistent with previous studies that have shown that therapeutic RNAi targeting PCSK9 has a significant effect on cardiovascular disease. Rapamycin, a medicine which reduces LDL cholesterol in mice and lowers LDL cholesterol levels in nonhuman primates, is one example. For these reasons, PCSK9 is a biomarker that is effective in atherosclerosis.
PMID: 12897189 by Maxwell K.N., et al. Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice.
PMID: 12552133 by Seidah N.G., et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.
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