Oxysterols are molecules derived from oxidized cholesterol. They are naturally present in the human body and found in various food sources. Although structurally similar to cholesterol, added oxygen atoms give them distinct properties and functions.
Understanding Oxysterols
Oxysterols form when cholesterol undergoes oxidation. This can occur through enzymatic reactions, mediated by enzymes like the cytochrome P450 (CYP) family, or through non-enzymatic processes involving reactive oxygen species. For example, 24-hydroxycholesterol (24-HC) and 27-hydroxycholesterol (27-HC) are common enzymatically formed oxysterols.
Oxysterols are also introduced through diet, particularly from foods containing oxidized cholesterol. Their formation often results from food processing, storage, and cooking methods involving heat and oxygen exposure, such as deep-frying. Many types of oxysterols exist, with oxidation occurring on the side chain, in the rings, or both, leading to compounds like 7-ketocholesterol (7-KC) or 7α-hydroxycholesterol (7α-HC).
How Oxysterols Function
Oxysterols play varied roles, particularly in regulating cholesterol metabolism. They act as feedback regulators of cholesterol synthesis by influencing enzymes like 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). When cellular cholesterol levels are high, certain oxysterols can interact with proteins such as SREBP-cleavage activating protein (SCAP) and INSIG, which suppresses cholesterol synthesis and uptake.
These compounds also promote cholesterol efflux from cells, especially from macrophages in arterial walls, aiding cholesterol removal from peripheral tissues. Oxysterols serve as signaling molecules, interacting with nuclear receptors like liver X receptors (LXRs). When activated by oxysterols, LXRs regulate the expression of genes involved in lipid metabolism and reverse cholesterol transport, maintaining cellular cholesterol balance.
Oxysterols are also involved in bile acid synthesis, acting as intermediates. For instance, LXR activation by specific oxysterols can increase CYP7A activity, leading to the production of 7α-HC, a precursor for bile acids. Beyond lipid regulation, oxysterols influence cell membrane integrity and participate in cellular signaling pathways, including those related to inflammation and immune responses.
Oxysterols and Disease
Oxysterols have been linked to the development and progression of several health conditions, with their role often depending on type and concentration. In atherosclerosis, the buildup of plaque, increased levels of oxysterols like 27-HC, 7-KC, and 7α-HC have been found in atherosclerotic lesions and foam cells. Some oxysterols, such as 27-HC, can promote atherosclerosis by upregulating inflammatory pathways in vascular cells and increasing macrophage accumulation.
Neurodegenerative diseases, including Alzheimer’s and Parkinson’s, also show connections to oxysterols. For example, 24-hydroxycholesterol has been linked to multiple sclerosis. In Alzheimer’s disease, oxysterols are implicated through their regulation of cholesterol synthesis and modulation of inflammatory responses, and 27-hydroxycholesterol can suppress a protein important for memory.
Oxysterols also play a role in certain types of cancer by influencing cell proliferation or apoptosis. Some, like 25- and 27-hydroxycholesterol, can increase estrogen receptor target gene transcription in breast cancer models, suggesting a role in resistance to hormonal therapy. Furthermore, oxysterols contribute to inflammatory conditions by inducing the expression of inflammatory cytokines, chemokines, and adhesion molecules.
Managing Oxysterol Levels
Dietary choices and cooking methods influence oxysterol levels in food. Foods rich in cholesterol, especially animal products, are primary sources of oxysterols when subjected to oxidation. High-temperature cooking, such as frying, significantly increases oxysterol formation. Microwaving chicken and beef produces about twice as much cholesterol oxidation as frying, while grilling may be safer if consumed immediately.
Reheating leftovers can also increase oxysterol levels. Beyond heat, exposure to pro-oxidant agents like light contributes to their formation. To reduce exogenous oxysterol intake, minimize consumption of processed foods and fried items.
Incorporating antioxidants into the diet helps mitigate oxysterol formation. Plant foods are rich in compounds with antioxidant properties, such as tocopherols, carotenoids, and phenolic compounds. Reducing cholesterol content in food sources, such as by not cooking with cholesterol-containing fats, can also help. Storing food in oxygen-excluding or opaque packaging and at low temperatures limits oxysterol formation.