Local researchers have identified how proprotein convertase subtilisin/kexin type-9 (PCSK9) decided the degrading mechanism of low-density lipoprotein (LDL)-receptor, which they said was for the first time in the world.
|Professors Kim Hyo-soo (left) and Jang Hyun-duk of Seoul National University Hospital|
The research team, led by Professors Kim Hyo-soo and Jang Hyun-duk at Seoul National University Hospital’s Research-centered Hospital Inflammation/Metabolism Unit, said they found that cyclase-associated protein 1 (CAP1) was essential for PCSK9 to destroy LDL-receptor and identified the mechanism.
When LDL-cholesterol combines with the LDL-receptor on the surface of hepatocytes, it enters the hepatocytes through an intracellular inflow pathway called clathrin. LDL-cholesterol is degraded and LDL-receptor is transported back to the cell surface for recycling.
Then, CAP1 drags PCKS9 bound to LDL-receptor to caveolin, an intracellular inflow pathway, so that LDL-receptor cannot be recycled and degraded through lysosomes.
In conclusion, CAP1 was essential for PCSK9 to degrade LDL-receptor, the research team said.
The team generated CAP1-inactivated mice and found that the mice without CAP1 had higher levels of LDL-receptor at the surface of hepatocytes and lower LDL-C levels in the blood than the normal mice.
The researchers also analyzed PCSK9 gene mutations in people with significantly lower LDL-cholesterol. The results showed that mutated PCSK9 was impaired in binding to CAP1.
As their PCSK9 failed to bind to CAP1, the good role of LDL-receptor remained intact, and they maintained a significantly low level of LDL-cholesterol, the researchers said.
The research team is working on a selective inhibitor that blocks the action of CAP1 and checking on whether the inhibitor can alleviate symptoms of metabolic diseases such as hyperlipidemia and fatty liver.
“We have identified the mechanism of a PCSK9 inhibitor antibody that significantly reduces patients’ cholesterol levels and mortality, for the first time. This provides an opportunity to develop a new drug,” Kim said. “Based on this, we’re speeding up new drug development.”
The researchers achieved the outcome after spending over five years for the study, which was sponsored by the Ministry of Health and Welfare’s Research-centered Hospital Project Inflammation/Metabolism Unit Program. The research was also published in the online version of the European Heart Journal.