PCSK9: Difference between revisions
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====Regulation==== | ====Regulation==== | ||
PCSK9 and LDL | PCSK9 and LDL receptors are chiefly regulated via the transcription factor sterol-responsive element-binding protein 2 (SREBP2), a pathway also induced by statins<ref name="Lambert-2007">{{Cite journal | last1 = Lambert | first1 = G. | title = Unravelling the functional significance of PCSK9. | journal = Curr Opin Lipidol | volume = 18 | issue = 3 | pages = 304-9 | month = Jun | year = 2007 | doi = 10.1097/MOL.0b013e3281338531 | PMID = 17495605 }}</ref> and an experimental [[resistin]]<ref name="Melone-2012">{{Cite journal | last1 = Melone | first1 = M. | last2 = Wilsie | first2 = L. | last3 = Palyha | first3 = O. | last4 = Strack | first4 = A. | last5 = Rashid | first5 = S. | title = Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9. | journal = J Am Coll Cardiol | volume = 59 | issue = 19 | pages = 1697-705 | month = May | year = 2012 | doi = 10.1016/j.jacc.2011.11.064 | PMID = 22554600 }}</ref> which is an adipose-tissue derived adipokine. Another regulator of the PCSK9 gene expression is the hepatic nuclear factor 1 alpha (HNF1a), a transcription factor activated in the liver cells.<ref name="Dong-2010">{{Cite journal | last1 = Dong | first1 = B. | last2 = Wu | first2 = M. | last3 = Li | first3 = H. | last4 = Kraemer | first4 = FB. | last5 = Adeli | first5 = K. | last6 = Seidah | first6 = NG. | last7 = Park | first7 = SW. | last8 = Liu | first8 = J. | title = Strong induction of PCSK9 gene expression through HNF1alpha and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters. | journal = J Lipid Res | volume = 51 | issue = 6 | pages = 1486-95 | month = Jun | year = 2010 | doi = 10.1194/jlr.M003566 | PMID = 20048381 }}</ref> PCSK9 has medical significance because it acts in cholesterol synthesis. Drugs that block PCSK9 can lower cholesterol, and are beginning Phase III clinical trials to see if they can improve outcomes in heart disease.<ref name=pollack>{{cite web | url =http://www.nytimes.com/2012/11/06/business/new-drugs-for-lipids-set-off-race.html | title = New Drugs for Lipids Set Off Race | author = Pollack A | date = November 5, 2012 | work = | publisher = New York Times }}</ref> | ||
==Clinical Significance== | ==Clinical Significance== | ||
Revision as of 17:07, 22 November 2013
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme encoded by the PCSK9 gene. PCSK9 has medical significance because it acts in cholesterol synthesis. Drugs that block PCSK9 can lower cholesterol, and are beginning Phase III clinical trials to see if they can improve outcomes in heart disease.
Historical Perspective
The role of PCSK9 was first discovered in 2003 when the cause of familial hypercholesterolemia in some french families was found to be associated with a 'gain of function' (leading to overproduction) mutation of PCSK9 gene.[1] Two years later, a causative association was found between 'loss of function' mutations in PCSK9 and low LDL-C levels in 2% of the African-American population but rare in European Americans (<0.1%), which were associated with a 40% reduction in plasma levels of LDL cholesterol.[2]
Structure, Function and Regulation
Structure
Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is a serine protease that in humans is encoded by the PCSK9 gene.[3] PCSK9 encodes a 692 amino acid protein that is expressed mainly in the liver, intestine, and kidney.[4] This gene encodes a proprotein convertase belonging to the proteinase K subfamily of the secretory subtilase family. The encoded protein is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. The protein may function as a proprotein convertase, and also plays a major regulatory role in cholesterol homeostasis.
Function
PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR), inducing LDLR degradation in the lysosomes. Reduced LDL receptor levels result in decreased metabolism of low-density lipoproteins (LDL), which could lead to hypercholesterolemia.[5] PCSK9 also have a role in the differentiation of cortical neurons,[3] and may also modulate apoB-containing lipoprotein production, independently of the LDL receptors.[6]
Regulation
PCSK9 and LDL receptors are chiefly regulated via the transcription factor sterol-responsive element-binding protein 2 (SREBP2), a pathway also induced by statins[7] and an experimental resistin[8] which is an adipose-tissue derived adipokine. Another regulator of the PCSK9 gene expression is the hepatic nuclear factor 1 alpha (HNF1a), a transcription factor activated in the liver cells.[9] PCSK9 has medical significance because it acts in cholesterol synthesis. Drugs that block PCSK9 can lower cholesterol, and are beginning Phase III clinical trials to see if they can improve outcomes in heart disease.[10]
Clinical Significance
PCSK9 Inhibitors
Increased low-density lipoprotein cholesterol (LDL-C) levels in the plasma is associated with the development and progression of atherosclerosis and associated diseases such as myocardial infarction and stroke. LDL receptors, which are responsible for clearing LDL-C from the circulation, get recycled back into the plasma membrane in order to bind more LDL-C. A novel approach to lipid management focuses on inhibiting the serine protease PCSK9 which is involved in the degradation of LDL receptors subsequently preventing the binding of new LDLs to be cleared from the circulation. [11][12][13][14]
Click here for more information about PCSK9 inhibition.
PCSK9 Deficiency
Following the deficiency of proprotein convertase subtilisin/kexin type 9 (PCSK9), a complete absence of degradation of LDL receptors occurs. This might lead to an uncontrolled uptake of LDL into the cells through the LDL receptors, leading to a fall in the plasma LDL level.
Autosomal Dominant Hypercholesterolemia
References
- ↑ Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C (2003). "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia". Nat. Genet. 34 (2): 154–6. doi:10.1038/ng1161. PMID 12730697. Unknown parameter
|month=ignored (help) - ↑ Cohen, J.; Pertsemlidis, A.; Kotowski, IK.; Graham, R.; Garcia, CK.; Hobbs, HH. (2005). "Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9". Nat Genet. 37 (2): 161–5. doi:10.1038/ng1509. PMID 15654334. Unknown parameter
|month=ignored (help) - ↑ 3.0 3.1 Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M (2003). "The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation". Proc. Natl. Acad. Sci. U.S.A. 100 (3): 928–33. doi:10.1073/pnas.0335507100. PMC 298703. PMID 12552133. Unknown parameter
|month=ignored (help) - ↑ Zaid, A.; Roubtsova, A.; Essalmani, R.; Marcinkiewicz, J.; Chamberland, A.; Hamelin, J.; Tremblay, M.; Jacques, H.; Jin, W. (2008). "Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration". Hepatology. 48 (2): 646–54. doi:10.1002/hep.22354. PMID 18666258. Unknown parameter
|month=ignored (help) - ↑ *"The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol". 2012-11-11.
- ↑ Sun, H.; Samarghandi, A.; Zhang, N.; Yao, Z.; Xiong, M.; Teng, BB. (2012). "Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor". Arterioscler Thromb Vasc Biol. 32 (7): 1585–95. doi:10.1161/ATVBAHA.112.250043. PMID 22580899. Unknown parameter
|month=ignored (help) - ↑ Lambert, G. (2007). "Unravelling the functional significance of PCSK9". Curr Opin Lipidol. 18 (3): 304–9. doi:10.1097/MOL.0b013e3281338531. PMID 17495605. Unknown parameter
|month=ignored (help) - ↑ Melone, M.; Wilsie, L.; Palyha, O.; Strack, A.; Rashid, S. (2012). "Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9". J Am Coll Cardiol. 59 (19): 1697–705. doi:10.1016/j.jacc.2011.11.064. PMID 22554600. Unknown parameter
|month=ignored (help) - ↑ Dong, B.; Wu, M.; Li, H.; Kraemer, FB.; Adeli, K.; Seidah, NG.; Park, SW.; Liu, J. (2010). "Strong induction of PCSK9 gene expression through HNF1alpha and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters". J Lipid Res. 51 (6): 1486–95. doi:10.1194/jlr.M003566. PMID 20048381. Unknown parameter
|month=ignored (help) - ↑ Pollack A (November 5, 2012). "New Drugs for Lipids Set Off Race". New York Times.
- ↑ Lopez D (2008). "Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia". Drug News Perspect. 21 (6): 323–30. doi:10.1358/dnp.2008.21.6.1246795. PMID 18836590.
- ↑ Steinberg D, Witztum JL (2009). "Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels". Proc. Natl. Acad. Sci. U.S.A. 106 (24): 9546–7. doi:10.1073/pnas.0904560106. PMC 2701045. PMID 19506257. Unknown parameter
|month=ignored (help) - ↑ Mayer G, Poirier S, Seidah NG (2008). "Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels". J. Biol. Chem. 283 (46): 31791–801. doi:10.1074/jbc.M805971200. PMID 18799458. Unknown parameter
|month=ignored (help) - ↑ "Bristol-Myers Squibb selects Isis drug targeting PCSK9 as development candidate for prevention and treatment of cardiovascular disease". Press Release. FierceBiotech. 2008-04-08. Retrieved 2010-09-18.