New oral drug for lowering cholesterol in Cell Reports

Currently, only statins are used to lower cholesterol, and after statins, the next major class of drugs to control cholesterol is PCSK9 inhibitors
.
These highly effective drugs can help the body remove excess cholesterol from the blood, but unlike statins, PCSK9 inhibitors can only be used as injections, which creates barriers
to their use.

Now, a new study from researchers at University Hospital (UH) and Case Western Reserve University School of Medicine describes an oral small molecule drug that can lower PCSK9 levels and lower cholesterol
by 70 percent in animal models.
The findings, published in Cell Reports, represent a previously unrecognized strategy for controlling cholesterol that may also influence cancer treatment
.

"Lowering cholesterol is one of the most important treatments we can use to prolong life and protect people from heart disease, which remains the number one cause
of morbidity and mortality in the Western world.
" Jonathan S.
Stamler, senior author at Harvard's Harrington Institute for Discovery and a professor of
medicine and biochemistry at Harvard's Case Western Reserve School of Medicine.
It's a new way to lower cholesterol, a new way
to combat PCSK9.

Study results

At the heart of cholesterol regulation is the low-density lipoprotein receptor, which sits on the surface of liver cells and removes cholesterol from the blood, thereby lowering serum levels
.
PCSK9 in the blood controls their number
by labeling degradation of LDL receptors.
Thus, drugs that inhibit PCSK9 increase the number of LDL receptors, which remove cholesterol
.

Nitric oxide is known to be a molecule
that prevents heart attacks by dilating blood vessels.
In the new study, Stamler and his colleagues show that nitric oxide can also target and inhibit PCSK9, thereby lowering cholesterol
.
They found a small molecule drug that works to increase nitric oxide inactivation
of PCSK9.
The "bad" cholesterol of the treated mice had a 70 percent
reduction in low-density lipoprotein (LDL) cholesterol.

The relationship between cholesterol and cancer

In addition to affecting the field of cholesterol metabolism, the findings may affect cancer patients because of new evidence that targeting PCSK9 can improve the efficacy
of cancer immunotherapy.

Stamler said: "PCSK9 not only targets the LDL receptor for degradation, it also mediates the degradation of MHC 1 on lymphocytes, which is used to recognize cancer cells
.
PCSK9 can effectively block lymphocytes from recognizing cancer cells
.
So, if you inhibit PCSK9, you can enhance your body's monitoring
of cancer.
Perhaps one day, we will have the opportunity to apply these new drugs to this need
.
”

Colin T.
Stomberski, Nicholas M.
Venetos, Hua-Lin Zhou, Zhaoxia Qian, Bryce R.
Collison, Seth J.
Field, Richard T.
Premont, Jonathan S.
Stamler.
A multienzyme S-nitrosylation cascade regulates cholesterol homeostasis.
Cell Reports, 2022; 41 (4): 111538