7-Ketocholesterol | Elisa - Clia - Antibody - Protein

Background

7-Ketocholesterol (7-KC) is an oxidized derivative of cholesterol. It is produced through the oxidative modification of cholesterol, particularly in the presence of reactive oxygen species (ROS) or other free radicals. The addition of an oxygen atom at the 7-position of the cholesterol molecule leads to the formation of 7-ketocholesterol. This modification can occur under conditions of oxidative stress, such as during inflammation, aging, or certain diseases.

7-Ketocholesterol is recognized as a bioactive lipid molecule with significant implications for various biological processes, particularly in cell signaling, inflammation, and neurodegenerative diseases. It is considered a pro-atherogenic and pro-inflammatory molecule, and its accumulation in tissues has been implicated in several conditions, including atherosclerosis, Alzheimer's disease, and age-related macular degeneration (AMD).

One of the notable concerns with 7-Ketocholesterol is its toxicity, especially its ability to induce cellular damage, promote oxidative stress, and contribute to neuroinflammation. Its role in lipid peroxidation is also of interest because the oxidative modification of lipids, including cholesterol, plays a crucial part in the pathogenesis of various diseases.

Chemical Structure

7-Ketocholesterol is a modified form of cholesterol where a keto group (C=O) is attached at the 7-position of the steroid ring structure. Cholesterol, a hydrophobic steroid, consists of four fused rings (three six-membered rings and one five-membered ring), with a hydroxyl group at the 3-position and a hydrocarbon tail.

The key chemical change in 7-KC is the presence of a carbonyl group (C=O) at the 7-position of the steroid ring. This modification alters the physicochemical properties of cholesterol, including its solubility, membrane incorporation, and biological activity.

• Molecular Formula: C27H44O2
• IUPAC Name: (3β)-cholest-5-en-7-one
• Molecular Weight: 398.64 g/mol

The carbonyl group at the 7-position is a key feature that distinguishes 7-Ketocholesterol from native cholesterol. This structural alteration leads to changes in how 7-KC interacts with various cellular components and how it is metabolized by enzymes.

Formation and Sources

7-Ketocholesterol is primarily produced through the oxidation of cholesterol, which occurs via the action of reactive oxygen species (ROS) or free radicals. Several factors can lead to the generation of 7-Ketocholesterol, including:

1. Oxidative Stress: The presence of oxidative stress in cells or tissues, such as in aging, inflammation, and hyperlipidemia, can lead to the oxidation of cholesterol. The production of ROS, including hydroxyl radicals and peroxyl radicals, facilitates the formation of various oxidized cholesterol derivatives, including 7-Ketocholesterol.
2. Enzymatic Oxidation: In addition to oxidative stress, 7-Ketocholesterol can also be produced enzymatically. Cytochrome P450 enzymes, lipoxygenases, and cyclooxygenases are involved in the oxidation of cholesterol, with cytochrome P450 enzymes particularly implicated in the generation of 7-Ketocholesterol.
3. Dietary Sources: While the body primarily generates 7-Ketocholesterol from its own cholesterol stores, dietary cholesterol, particularly from animal fats, can also contribute to the pool of cholesterol available for oxidation. Dietary fats and the presence of unsaturated fatty acids can influence lipid peroxidation and the formation of oxidized cholesterol derivatives, including 7-Ketocholesterol.

Biological Significance and Function

7-Ketocholesterol has been shown to have significant biological effects due to its ability to modify cellular functions, disrupt cellular membranes, and influence cellular signaling pathways:

1. Pro-Atherogenic Effects: 7-Ketocholesterol has been implicated in the development of atherosclerosis, a condition characterized by the buildup of plaques in the arteries. 7-KC contributes to the formation of foam cells, a hallmark of atherosclerotic lesions, by promoting the accumulation of oxidized low-density lipoprotein (LDL) and causing endothelial cell damage. It also increases the oxidative stress and inflammation in blood vessels, further contributing to the pathogenesis of atherosclerosis.
2. Neurotoxicity and Alzheimer's Disease: 7-Ketocholesterol is considered neurotoxic due to its ability to induce oxidative stress and promote the formation of beta-amyloid plaques, which are a hallmark of Alzheimer’s disease (AD). 7-KC can also disrupt neuronal membranes, impair synaptic function, and activate microglial cells, leading to neuroinflammation. These processes contribute to the neurodegenerative damage observed in AD and other neurodegenerative diseases.
3. Inflammation and Immune Response: 7-Ketocholesterol has potent pro-inflammatory properties. It can stimulate the production of pro-inflammatory cytokines and chemokines, activate macrophages, and influence immune cell signaling. This makes 7-KC a key molecule in inflammatory diseases, contributing to tissue damage in conditions such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
4. Lipid Peroxidation: 7-Ketocholesterol is both a product and a driver of lipid peroxidation. As an oxidized derivative of cholesterol, 7-KC can further interact with cellular lipids, initiating the formation of additional reactive oxygen species (ROS) and lipid peroxides. This positive feedback loop accelerates oxidative damage to lipids, proteins, and DNA, contributing to cellular dysfunction and death.
5. Altered Membrane Properties: 7-Ketocholesterol can alter the physical properties of cellular membranes, making them more rigid and less fluid. This can disrupt the function of membrane-bound proteins and enzymes, impair cell signaling, and affect the ability of cells to maintain homeostasis.

Clinical Implications and Disease Associations

Given its role in oxidative stress, inflammation, and neurodegeneration, 7-Ketocholesterol has been implicated in a range of diseases and conditions:

1. Atherosclerosis: Elevated levels of 7-Ketocholesterol have been associated with increased oxidative stress in arterial plaques. By promoting the oxidation of LDL and contributing to foam cell formation, 7-KC accelerates the development of atherosclerotic lesions, leading to heart disease, stroke, and peripheral artery disease.
2. Alzheimer's Disease (AD): 7-Ketocholesterol is involved in the pathogenesis of Alzheimer's disease, contributing to neuroinflammation, oxidative damage, and the formation of beta-amyloid plaques. Elevated levels of 7-KC in the brain are thought to play a role in the progression of Alzheimer's disease and other forms of neurodegeneration.
3. Cancer: The accumulation of oxidized cholesterol derivatives, including 7-Ketocholesterol, has been associated with cancer progression. 7-KC can promote cellular transformation, induce inflammation, and affect tumor microenvironments, which can enhance tumor growth and metastasis.
4. Age-Related Macular Degeneration (AMD): 7-Ketocholesterol has been identified as a contributing factor in the development of AMD, an eye disease that leads to the deterioration of the macula. It is thought that 7-KC can induce oxidative stress in retinal cells, contributing to the pathology of AMD.
5. Neurodegenerative Diseases: In addition to Alzheimer's, other neurodegenerative diseases, such as Parkinson's disease and multiple sclerosis, have been linked to oxidative stress and lipid peroxidation. 7-Ketocholesterol’s neurotoxic properties could contribute to neuronal degeneration and disease progression.

Summary

7-Ketocholesterol is an oxidized derivative of cholesterol that plays a significant role in various biological processes, particularly in inflammation, oxidative stress, and neurodegeneration. It is a potent pro-atherogenic and pro-inflammatory molecule that contributes to the development of conditions such as atherosclerosis, Alzheimer’s disease, and age-related macular degeneration (AMD). 7-KC’s ability to induce oxidative damage, lipid peroxidation, and cellular dysfunction makes it a key factor in the pathogenesis of these diseases. Further research into the mechanisms through which 7-Ketocholesterol influences disease processes could provide insights into novel therapeutic strategies for managing conditions associated with oxidative stress and lipid metabolism disorders.