March 2019
Lipid Club Newsletter

LCL jan 2012

Inhibition of PCSK9
(proprotein convertase subtilisin/kexin type 9) :
an exciting therapeutic development.

Jean Ducobu(UMons) adapted from :
“ Inhibition of PCSK9: A powerful weapon for achieving ideal LDL cholesterol levels” Daniel Steinberg and
Joseph L. Witztum PNAS June 16, 2009 vol. 106 no. 24 9546-9547

The LDL cholesterol level is a major determinant of cardiovascular disease (CVD) risk. The striking results of the large-scale statin trials showed that LDL levels can be reduced by 30–40% with comparable percentage reductions in CVD risk and support the concept that ‘‘the lower the LDL the better’’ is a reasonable position.
However, achieving LDL levels of 70 mg/dL or lower in patients with high initial values is often not possible with statins alone, even with maximum dosages.It needs often combination with other drugs (like ezetimibe). Consequently,the search for new cholesterol-lowering interventions is mandatory.

The number of LDL-R expressed on the surface of hepatocytes is the primary determinant of plasma LDL levels.It binds plasma LDL on the hepatocyte surface, mediating LDL uptake and delivery to the endosomal system, where the LDL particle is released, and the LDL-R is recycled back to the hepatocyte surface to bind LDL particles.

The PCSK9 (“proprotein convertase subtilisin/kexin type 9.”)protein appears to control the number of low-density lipoprotein receptors,which determines how quickly cholesterol (in the form of low-density lipoproteins) is removed from the bloodstream. Studies suggest that the PCSK9 protein helps control blood cholesterol levels by breaking down low-density lipoprotein receptors before they reach the cell surface. In the hepatocyte, PCSK9 undergoes an obligatory autocatalytic cleavage in the endoplasmic reticulum before being secreted, but its catalytic activity is not required for its ability to modulate LDL-R surface expression. Its 3 dimensional structure is described on figure 1

Figure 1

Rather, PCSK9 is secreted into plasma by hepatocytes and acts by binding to the LDL-R extracellularly, being internalized with it and facilitating its enhanced degradation. PCSK9 does not itself degrade the LDL-R but binds tightly to it and channels it toward the lysosomal compartment for degradation.(fig 2)
Thus, it inhibits the recycling of the LDL-R back to the cell surface, which results in decreased LDL-R number and increased plasma LDL levels.

Figure 2


In PCSK9-/- KO mice,,LDL levels decrease because LDL receptors are more abundant on membranes surfaces.(fig 3)

Figure 3

And the plasma clearance of LDL decrease more than in Wild –type mice. (fig 4)

Figure 4

On the contrary ,overerexpression of PCSK9 in mice enhance hepatocyte degradation of the LDL-R, resulting in dramatic elevations of plasma LDL.

How are changes in the PCSK9 gene related to human health conditions?

Researchers have identified several PCSK9 mutations that cause an inherited form of high cholesterol (hypercholesterolemia). These mutations change a single protein building block (amino acid) in the PCSK9 protein. Researchers describe the mutations responsible for hypercholesterolemia as "gain-of-function" because they appear to enhance the activity of the PCSK9 protein or give the protein a new, atypical function.
The overactive PCSK9 protein significantly reduces the number of low-density lipoprotein receptors on the surface of liver cells.. With fewer receptors to remove low-density lipoproteins from the blood, people with gain-of-function mutations in the PCSK9 gene have very high blood cholesterol levels.