New mechanism to control bad cholesterol!

New mechanism to control bad cholesterol!
 

More than 600,000 Danes are being treated with cholesterol lowering medicine. 98 per cent of them are treated with statins, which curb the body's own production of cholesterol so that the level of cholesterol falls. However, statins also give rise to the body forming more of a harmful protein - known as PCSK9 - which counters the effect of the statins. New research has now uncovered the way in which PCSK9 breaks down the LDL receptors, which are a kind of receptor molecule that absorbs the bad LDL cholesterol in the blood into the liver.

This discovery makes it possible to develop potentially more efficient and also cheaper PCSK9 inhibiting medicine, which is the new hope for cholesterol treatment.

Authors show that liver heparan sulfate proteoglycans are PCSK9 receptors and essential for PCSK9-induced LDLR degradation. The heparan sulfate-binding site is located in the PCSK9 prodomain and formed by surface-exposed basic residues interacting with trisulfated heparan sulfate disaccharide repeats.

Researchers demonstrate heparan sulfate mimetics and monoclonal antibodies directed against the heparan sulfate-binding site are potent PCSK9 inhibitors. They propose that heparan sulfate proteoglycans lining the hepatocyte surface capture PCSK9 and facilitates subsequent PCSK9:LDLR complex formation.

"Statins save many lives every year, but the medicine has the unfortunate consequence that the liver cells begin to produce more PSCK9. We have now uncovered how PCSK9 is captured by specific molecules in the liver called heparan sulfate proteoglycans (HSPG), which subsequently lead to the breaking down of the LDL receptor. The consequence is less LDL receptor in the liver, higher LDL cholesterol in the blood and an increased risk of blood clots in the heart. If this process is inhibited, the LDL receptor is protected against degradation, and the amount of cholesterol in the blood falls," says the senior author.

With the discovery, the researchers have provided one of the pieces that has been missing in the puzzle of understanding PCSK9, and this opens up for the development of a new type of medicine that can potentially work far better than statins. The research result has just been published in the journal Nature Communications.

PCSK9 inhibiting medicine is already available on the market, but due to high costs it is only offered to patients who are particularly at risk, as well as those who do not have benefit from or are intolerant to statins. Using the new knowledge about PCSK9, the researchers from Aarhus have begun to develop new medicine that is now ready for the first tests on patients.4

https://www.nature.com/articles/s41467-017-00568-7

Edited

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