A group of researchers, including Matthew O’Connor of Cyclarity Therapeutics, has published a review detailing what effects 7-ketocholesterol (7KC) has in the human body.
An oxidized cholesterol
7KC, an oxidized cholesterol (oxysterol) gets its name from being oxidized at the C7 position within the cholesterol molecule [1]. This compound is formed by non-enzymatic processes driven by reactive oxygen species (ROS); like the collagen crosslinks of glucosepane, it is formed as a byproduct rather than something that the body has any use for [2].
The 7KC non-enzymatic modification can also be formed as part of cholesterols that were oxidized enzymatically. This review names 25-hydroxycholesterol (25-OHC) and 27-hydroxycholesterol (27-OHC) as two of the most important, which can become 7-keto-25-OHC and 7-keto-27-OHC, respectively. However, this paper notes that little research has been done into these two compounds, making them potential targets for future work.
Foam cells and beyond
7KC is widely found within artherosclerotic lesions, moreso than other oxysterols [3], and it has several well-known negative effects. Probably the most concerning of these is that it cannot be properly digested by macrophages [1]; when macrophages ingest enough 7KC, they become foam cells, which cause further damage to tissues by excreting inflammatory factors, including a wide variety of interleukins such as IL-1β [4].
Foam cells also become much more prone to ingesting lipids, which bloat them further and prevent them from digesting other molecules [5]. The resulting accumulation of lipid-filled foam cells within the arteries is well-known as a core driver of cardiovascular disease and a major contributor to ischemias, such as strokes and heart attacks.
Foam cells, however, are not the only danger of 7KC. This review notes that 7KC is particularly toxic to neurons; neurons that take up 7KC sustain damage to their nuclei and have increased levels of caspase-3, a compound that leads to their death [6]. Similarly, 7KC also promotes lipid accumulation in neurons along with myelin figures that lead to death by apoptosis [7].
There are other, broader dangers as well. As it damages the mitochondria, 7KC encourages the production of further ROS, compounding the initial problem and reducing the cellular ability to handle cholesterol at all [8]. 7KC within cells has also been found to impair the cellular maintenance process known as autophagy, by which cells would normally consume malfunctioning components [9].
7KC as a biomarker
Because it is so strongly tied to oxidative stress and cardiovascular disease, this paper devotes a section for discussing 7KC’s potential value as a biomarker. While cholesterol, including LDL and HDL cholesterol, is well-known as a biomarker, there is no currently accepted blood assay for detecting 7KC the way there is for many other harmful circulating compounds. This, the researchers lament, is due to a “lack of standardized, scalable, and cost-effective measurement techniques.” Creating such techniques would allow for both a systemic analysis along with organ-specific analyses that detect potential damage to the brain, liver, and vascular tissue.
Dealing with 7KC
The human body has evolved some limited protections against 7KC accumulation. Within the liver, liver X receptor (LXR) along with oxysterol-binding-proteins (OSBPs) are activated in response, and this has been demonstrated to have some benefits for neurons [10]. However, the complete effects of these two secretions against 7KC in the human body are not fully known.
This paper notes that several compounds, such as flavonoids and other broad-spectrum antioxidants, have been investigated as potential treatments for 7KC. However, there are several shortcomings; these compounds lack specificity for 7KC, are poorly taken up by the body, and do not penetrate tissues, meaning that they fail to achieve statistically significant effects against oxysterol accumulation in living organisms. Targeting oxidative stress itself through a variety of means may have some limited effects, but, because oxidative stress occurs throughout the body due to a wide variety of causes, this paper holds that “it is likely that the effect would not be robust enough to meaningfully impact 7KC levels system-wide.”
Other methods involve using drugs to target oxidized cholesterol more directly. However, this paper further holds that “it will certainly not reverse foam cell formation”, as such drugs can only affect circulating oxidized cholesterol rather than 7KC that has already been taken up into cells.
To accomplish that, Cyclarity Therapeutics intends to use a cyclodextrin that is specific to 7KC and is able to pull it from cells. This paper suggests that this approach, currently in a Phase 1 clinical trial as UDP-003, is more effective than 2-hydroxypropyl-β-cyclodextrin (HPBCD), another compound that binds to 7KC [11]. Of course, only after it has passed through the clinical trial process will we be able to say for sure.
Literature
[1] Anderson, A., Campo, A., Fulton, E., Corwin, A., Jerome III, W. G., & O’Connor, M. S. (2020). 7-Ketocholesterol in disease and aging. Redox biology, 29, 101380.
[2] Nury, T., Yammine, A., Ghzaiel, I., Sassi, K., Zarrouk, A., Brahmi, F., … & Lizard, G. (2021). Attenuation of 7-ketocholesterol-and 7β-hydroxycholesterol-induced oxiapoptophagy by nutrients, synthetic molecules and oils: Potential for the prevention of age-related diseases. Ageing Research Reviews, 68, 101324.
[3] Hitsumoto, T., Takahashi, M., Iizuka, T., & Shirai, K. (2009). Clinical significance of serum 7-ketocholesterol concentrations in the progression of coronary atherosclerosis. Journal of atherosclerosis and thrombosis, 16(4), 363-370.
[4] Lemaire, S., Lizard, G., Monier, S., Miguet, C., Gueldry, S., Volot, F., … & Néel, D. (1998). Different patterns of IL-1β secretion, adhesion molecule expression and apoptosis induction in human endothelial cells treated with 7α-, 7β-hydroxycholesterol, or 7-ketocholesterol. FEBS letters, 440(3), 434-439.
[5] Maor, I., Mandel, H., & Aviram, M. (1995). Macrophage Uptake of Oxidized LDL Inhibits Lysosomal Sphingomyelinase, Thus Causing the Accumulation of Unesterified Cholesterol–Sphingomyelin–Rich Particles in the Lysosomes: A Possible Role for 7-Ketocholesterol. Arteriosclerosis, thrombosis, and vascular biology, 15(9), 1378-1387.
[6] Nury, T., Sghaier, R., Zarrouk, A., Menetrier, F., Uzun, T., Leoni, V., … & Lizard, G. (2018). Induction of peroxisomal changes in oligodendrocytes treated with 7-ketocholesterol: Attenuation by α-tocopherol. Biochimie, 153, 181-202.
[7] Vejux, A., Kahn, E., Dumas, D., Bessede, G., Ménétrier, F., Athias, A., … & Lizard, G. (2005). 7‐Ketocholesterol favors lipid accumulation and colocalizes with Nile Red positive cytoplasmic structures formed during 7‐ketocholesterol–induced apoptosis: Analysis by flow cytometry, FRET biphoton spectral imaging microscopy, and subcellular fractionation. Cytometry Part A: The Journal of the International Society for Analytical Cytology, 64(2), 87-100.
[8] Charles, K. N., Shackelford, J. E., Faust, P. L., Fliesler, S. J., Stangl, H., & Kovacs, W. J. (2020). Functional peroxisomes are essential for efficient cholesterol sensing and synthesis. Frontiers in cell and developmental biology, 8, 560266.
[9] Yuan, X. M., Sultana, N., Siraj, N., Ward, L. J., Ghafouri, B., & Li, W. (2016). Autophagy induction protects against 7-oxysterol-induced cell death via lysosomal pathway and oxidative stress. Journal of cell death, 9, JCD-S37841.
[10] Okabe, A., Urano, Y., Itoh, S., Suda, N., Kotani, R., Nishimura, Y., … & Noguchi, N. (2014). Adaptive responses induced by 24S-hydroxycholesterol through liver X receptor pathway reduce 7-ketocholesterol-caused neuronal cell death. Redox biology, 2, 28-35.
[11] Kritharides, L., Kus, M., Brown, A. J., Jessup, W., & Dean, R. T. (1996). Hydroxypropyl-β-cyclodextrin-mediated efflux of 7-ketocholesterol from macrophage foam cells. Journal of Biological Chemistry, 271(44), 27450-27455.
View the article at lifespan.io
