If the metabolic pathway uncovered in mice is found to operate similarly in humans, the new discovery could point the way to therapies that protect against heart disease by boosting concentrations of the beneficial high-density lipoprotein cholesterol (HDL-C).
Low-density lipoprotein cholesterol (LDL-C) can build up in blood vessel walls, increasing the risk of heart disease or stroke. By contrast, HDL-C tends to carry cholesterol away from the arteries to the liver, a process known as reverse cholesterol transport, where it is broken down and then eliminated from the body.
As part of the study, Weijun Jin and colleagues demonstrated that treatments that partially block the activity of liver enzymes called proprotein convertases decreased plasma HDL-C levels in mice.
The study showed that metabolic effect of the proprotein convertases depended on yet another factor, an enzyme called endothelial lipase (EL), which breaks down HDL-C.
Researchers noted that Proprotein convertases normally reduce EL function, thus the loss of proprotein convertase activity leads to an increase in EL and a decline in HDL-C.
Likewise, they showed that increased activity of proprotein convertases in the liver gave a significant boost to the protective HDL-C.
"Proprotein convertases are an unexpected new player in HDL-C metabolism. By manipulating levels of the enzyme in both directions, we were able to reduce HDL-C to almost nothing or double it. That wide range of effects suggests that it may be theoretically possible to manipulate good cholesterol levels to whatever point you like," Jin said.
The findings of the study were published in the August issue of Cell Metabolism, a publication of Cell Press.