A particularly harmful byproduct of oxidized cholesterol appears to be a primary cause of atherosclerosis and a therapeutic target ripe for the taking. A new review takes a look at 7-ketocholesterol and its role in aging and disease.

A new review exploring 7-ketocholesterol

We recently reported on the launch of Underdog Pharma, a new startup biotech company that was spun off from many years of research at SENS Research Foundation and is focused on the problem of 7-ketocholesterol.

Today, some of that work has been published in the form of a review that explores the role of 7-ketocholesterol in depth and provides insight into how and why it drives the development of atherosclerosis and other diseases.

Cholesterol is a critical organic molecule that facilitates a variety of functions in the body. It is a sterol (a modified steroid) and a type of lipid, a substance that is insoluble in water and soluble in alcohol, ether, and chloroform. Lipids are an important structural part of cell membranes, are easily stored within the body, and serve as a source of fuel.







Cholesterol comes in a variety of forms that exist inside and outside of our cells. In the bloodstream, they are transported by lipoprotein particles; perhaps the most well-known variety is low-density lipoprotein (LDL), which transports cholesterol around the body to our peripheral tissues.

7-ketocholesterol drives atherosclerosis

Unfortunately, LDL is vulnerable to oxidation, which leads to the creation of an oxidized form of LDL (OxLDL), which is associated with a number of diseases. During oxidation, LDL creates various byproducts, of which 7-ketocholesterol is the most common. In some animal studies, 7-ketocholesterol has been shown to be even more atherogenic than cholesterol, making it a serious contributor to heart attacks and strokes. It is also implicated in Alzheimer’s disease and macular degeneration.

7-ketocholesterol is highly toxic, and when an atherosclerotic lesion forms in the wall of an artery, our macrophages respond to the injury and arrive to clean away the unwanted lipids and debris lodged in the arterial wall. Unfortunately, macrophages are not very good at breaking down 7-ketocholesterol, and, eventually, they absorb so much that it shuts down their waste disposal systems, the lysosomes, rendering the affected macrophages no longer able to metabolize lipids.

However, despite being full, they continue to absorb more 7-ketocholesterol and become engorged, turning into what are known as foam cells, huge bloated cells that no longer work and can only signal for help as they slowly die. Their frantic calls for assistance attract more macrophages, which rush to the injury site to try to help, only for them to become bloated foam cells as well.







These dead and dying foam cells make up the bulk of atherosclerotic plaques and are an example of how our bodies harm themselves during aging even while they attempt to make repairs and remove the waste that hurts us; our macrophages mean well, but, sadly, they do not have the right tools for the job.

The new publication gives a very readable account of how 7-ketocholesterol contributes to the development of various diseases, particularly atherosclerosis, and how it has great potential as a target for therapeutic interventions designed to remove it from the body.

7-Ketocholesterol (7KC) is a toxic oxysterol that is associated with many diseases and disabilities of aging, as well as several orphan diseases. 7KC is the most common product of a reaction between cholesterol and oxygen radicals and is the most concentrated oxysterol found in the blood and arterial plaques of coronary artery disease patients as well as various other disease tissues and cell types. Unlike cholesterol, 7KC consistently shows cytotoxicity to cells and its physiological function in humans or other complex organisms is unknown. Oxysterols, particularly 7KC, have also been shown to diffuse through membranes where they affect receptor and enzymatic function. Here, we will explore the known and proposed mechanisms of pathologies that are associated with 7KC, as well speculate about the future of 7KC as a diagnostic and therapeutic target in medicine.

Conclusion

Underdog Pharma is now taking these findings forward to build a therapy capable of clearing out 7-ketocholesterol, and, if the company gets it right, it could potentially offer a solution to heart disease and more. If you would like to learn more about how Underdog Pharma is proposing to deal with the problem of 7KC, you may wish to check out our recent interview to celebrate the company’s launch.





