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LDL-C is normally cleared from the circulation as apoprotein B100 on the surface of LDL and binds to LDL receptors on hepatic and extrahepatic tissues.While statins effectively decrease cholesterol levels, their efficacy is diminished by this increase in PCSK9 activity.As the intracellular concentration of cholesterol increases, 3 events occur, as mentioned below.[9]

Decreased activity of 3-hydroxy-3-methylglutaryl coenzyme AHMG-CoA reductase--the rate-limiting enzyme of cholesterol synthesis.PCSK9, a product of hepatocytes, is secreted into the plasma, where it binds to the LDL receptors, facilitating their lysosomal degradation.Activation of acyl-coenzyme A:cholesterol acyltransferase (ACAT)--an enzyme that increases cholesterol storage as a cholesterol ester.

LDL-C is normally cleared from the circulation as apoprotein B100 on the surface of LDL and binds to LDL receptors on hepatic and extrahepatic tissues. LDL bound to these receptors undergoes a process of endocytosis. The endocytic vesicle fuses with lysosomes, increasing the intracellular concentration of free cholesterol. As the intracellular concentration of cholesterol increases, 3 events occur, as mentioned below.[9]

Decreased activity of 3-hydroxy-3-methylglutaryl coenzyme AHMG-CoA reductase—the rate-limiting enzyme of cholesterol synthesis.
Activation of acyl-coenzyme A:cholesterol acyltransferase (ACAT)—an enzyme that increases cholesterol storage as a cholesterol ester.
Reduced expression of LDL receptors on the cell surface.
In this highly integrated system, as the cell takes up more cholesterol by this normal LDL-receptor pathway, de novo production of cholesterol decreases, and less is taken up by the LDL receptors. When LDL levels are particularly high or undergo modification, such as glycation or oxidation, they are more apt to be taken up by the scavenger pathway on endothelial cells, leading to the development of atherosclerotic plaques and vascular disease.

An important concept to recognize is that LDL receptors continually recycle back to the cell surface, where they bind and clear more LDL-C. PCSK9, a product of hepatocytes, is secreted into the plasma, where it binds to the LDL receptors, facilitating their lysosomal degradation. Thus, PCSK9 reduces the expression of LDL receptors on the cell membrane, decreasing the clearance of LDL-C.

Statins decrease HMG-CoA reductase activity, reducing cholesterol synthesis. Reduced intracellular cholesterol leads to increased recycling and the expression of LDL receptors on the cell surface. This, in turn, allows for increased clearance of LDL-C by the non-atherogenic receptor-mediated pathway, leaving less LDL to be taken up by the scavenger pathway. Statins increase the activity of PCSK9. While statins effectively decrease cholesterol levels, their efficacy is diminished by this increase in PCSK9 activity.