PCSK9: A Recent Discovery in Understanding Cholesterol Regulation @ AMGEN Cardiovascular
Reporter: Aviva Lev-Ari, PhD, RN
UPDATED on 3/28/2016
· by Crystal Phend
Senior Associate Editor, MedPage Today
Alirocumab (Praluent) reduced the frequency of apheresis by 75% compared with placebo and eliminated the need for apheresis for 63%, according to top-line results from the 62-patient phase III ODYSSEY ESCAPE trial in heterozygous familial hypercholesterolemia getting the treatments.
SOURCE
UPDATED on 3/21/2016
The PPAR-delta agonist MBX-8025 was associated with a drop in LDL cholesterol by at least 15% for the majority of genetically-confirmed homozygous familial hypercholesterolemia patients when added to ezetimibe (Zetia) and maximal statin therapy in a small open-label, dose-escalation phase II trial. The company plans a pilot study combining the agent with a PCSK9 inhibitor too.
SOURCE
CVD = cardiovascular disease;
HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A;
LDL = low-density lipoprotein;
LDL-C = low-density lipoprotein cholesterol;
LDLR = low-density lipoprotein receptor;
PCSK9 = proprotein convertase subtilisin/kexin type 9.
References
- Brown MS, Goldstein JL. Proc Natl Acad Sci USA. 1979;76:3330-3337.
- Goldstein JL, Brown MS. Arterioscler Thromb Vasc Biol. 2009;29:431-438.
- Qian Y-W, Schmidt RJ, Zhang Y, et al. J Lipid Res. 2007;48:1488-1498.
- Brown MS, Goldstein JL. Science. 1986;232:34-47.
- Horton JD, Cohen JC, Hobbs HH. J Lipid Res. 2009;50(suppl):S172-S177.
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PCSK9 gene mutations can have profound effects on plasmaLDL-C levels1
PCSK9 Loss of Function Mutations
Increase LDLR levels on the surface of the hepatocyte, which leads to an increase in LDL clearance, resulting in low plasma LDL-C levels2,3
PCSK9 Gain of Function Mutations
Decrease LDLR levels on the surface of the hepatocyte, which leads to a reduction in LDL clearance, resulting in high plasma LDL-C levels2,3
- The Biology of Cholesterol Synthesis and Metabolism
HMG-COA REDUCTASE IS THE RATE-CONTROLLING ENZYME IN CHOLESTEROL BIOSYNTHESIS.1
Both HMG-CoA reductase and LDLRs are tightly regulated and can be increased or decreased, affecting cholesterol synthesis and homeostasis.2
Reductase
Incoming hepatic cholesterol suppresses HMG-CoA reductase, turning off cholesterol synthesis in the cell.1
In addition, LDLR synthesis is turned off, preventing further entry of LDL and protecting cells against an overaccumulation of cholesterol.1
Recycling of LDLRs enables efficient clearance of plasma LDL particles.2
LDLRs bind to LDL particles and transport them into the hepatocyte. The LDL particles then dissociate from the LDLRs and are broken down. The LDLRs are then free to recycle back to the cell surface and bind to additional LDL particles, clearing them from the blood.2 The ability of LDLRs to be recycled is key to the liver’s ability to lower plasma LDL-C levels.
PCSK9 regulates the recycling of LDLRs by targeting the LDLR for degradation3
While HMG-CoA reductase plays a critical role in cholesterol biosynthesis, PCSK9 plays a critical role in cholesterol metabolism.4,5 By promoting LDLR degradation within hepatocytes, PCSK9 reduces the concentration of LDLRs on the hepatocyte surface, resulting in increased plasma LDL-C levels.3
Over 20 related articles published on PCSK9 in Cholesterol Regulation on this Open Access Scientific Journal, include the following:
https://pharmaceuticalintelligence.com/?s=PCSK9
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