25-hydroxycholesterol (25-HC) is an oxidized derivative of cholesterol, known as an oxysterol. This molecule is an important signaling molecule throughout the body, influencing various physiological and pathological processes. Its ability to pass through cell membranes and vascular barriers allows it to act both locally and at distant sites. Its wide-ranging effects extend beyond simple cholesterol metabolism.
Formation and Basic Nature
25-hydroxycholesterol is chemically characterized as cholest-5-en-3β,25-diol. The primary method of its formation in the body involves the enzymatic conversion of cholesterol by cholesterol 25-hydroxylase (CH25H). This enzyme uses cholesterol, molecular oxygen, and NADPH to add a hydroxyl group at the 25th carbon position of cholesterol.
While CH25H is the main enzyme responsible for 25-HC biogenesis, non-enzymatic pathways can also generate this oxysterol. Human tissues typically contain very low levels of 25-HC under normal conditions, significantly less than other oxysterols like 27-HC or 24S-HC. However, its production can increase tenfold during inflammatory responses, particularly in macrophages, dendritic cells, and microglia.
Diverse Biological Functions
25-hydroxycholesterol plays multiple roles in the body, regulating various biological processes. Its influence extends to immune system regulation, lipid metabolism, and broader cell signaling pathways. The specific effects can vary depending on the cell type, the presence of viruses, and the surrounding cellular environment.
Immune System Regulation
25-HC influences immune cell activity and inflammatory responses. It is produced by immune cells in response to infection and can amplify the activation of these cells, leading to increased production of immune mediators. For example, 25-HC can mediate the recruitment of AP-1 components, such as FBJ osteosarcoma oncogene (FOS) and jun proto-oncogene (JUN), to the promoters of Toll-like receptor-responsive genes, thereby amplifying inflammatory signaling in macrophages.
Beyond its pro-inflammatory effects, 25-HC can also have anti-inflammatory functions. It inhibits the secretion of interleukin-1 beta (IL-1β) by suppressing inflammasomes. The balance of 25-HC’s pro- and anti-inflammatory roles is important for preventing excessive tissue damage. Macrophage activation by Toll-like receptors induces CH25H expression and 25-HC synthesis, which then acts as a suppressor of immunoglobulin A (IgA) class switching in B cells.
Lipid Metabolism and Cholesterol Homeostasis
25-HC is a regulator of lipid metabolism and cholesterol homeostasis, primarily by interacting with sterol regulatory element-binding proteins (SREBPs) and liver X receptors (LXRs). It functions by inhibiting SREBP processing, which in turn reduces the expression of enzymes involved in cholesterol biosynthesis, such as HMG-CoA reductase (HMGCR). This leads to a decrease in cholesterol synthesis and uptake by cells.
25-HC can also activate LXRs, a family of nuclear receptors that regulate cholesterol metabolism. LXR activation by 25-HC can induce the expression of genes like ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1), which are responsible for cholesterol efflux from cells. This dual action of suppressing cholesterol synthesis and promoting its efflux helps maintain intracellular cholesterol balance. However, some studies in mice lacking CH25H have questioned the overall impact of 25-HC on whole-body cholesterol metabolism, suggesting context-dependent effects.
Cell Signaling
Beyond its direct roles in immunity and lipid metabolism, 25-HC influences various cellular signaling pathways. It can bind to several proteins, including insulin-induced gene proteins (INSIG), Niemann-Pick protein C1 (NPC1), and oxysterol-binding protein (OSBP) family members, thereby affecting diverse cellular processes.
25-HC can also activate the endoplasmic reticulum-localized enzyme ACAT, leading to the internalization of accessible cholesterol on the plasma membrane. Additionally, 25-HC has been shown to induce inflammatory events through pathways like ME/ERK signaling, leading to the secretion of interleukin-8 (IL-8), and can also promote vascular endothelial growth factor (VEGF) production.
Role in Health and Disease
The diverse functions of 25-hydroxycholesterol mean it plays a role in various health conditions and diseases, often due to its involvement in inflammation and lipid regulation. The levels and activity of 25-HC are associated with inflammatory diseases, neurodegenerative disorders, viral infections, and certain cancers.
Inflammatory Diseases
25-HC is linked to inflammatory processes and autoimmune conditions. Its production is increased in macrophages, dendritic cells, and microglia during inflammatory responses. While it can amplify inflammatory signaling, its precise role in chronic inflammation is complex and context-dependent. For example, 25-HC produced by macrophages can accumulate in atherosclerotic lesions, promoting vascular inflammation and remodeling.
Elevated concentrations of 25-HC have been measured in the cerebrospinal fluid of patients with inflammatory central nervous system diseases, including suspected autoimmune conditions. The balance between its pro- and anti-inflammatory effects is important for disease outcomes.
Neurodegenerative Disorders
Research suggests links between 25-HC and neurodegenerative conditions like Alzheimer’s disease (AD). 25-HC is produced by cholesterol 25-hydroxylase (CH25H), an enzyme upregulated in AD brain models. Studies in mouse models of tauopathy, a feature of AD, show that reducing 25-HC levels by removing CH25H can decrease age-dependent neurodegeneration and neuroinflammation.
This suggests that 25-HC may enhance pro-inflammatory signaling in microglia, contributing to tau-mediated neurodegeneration. While 25-HC can promote neuroinflammation and is involved in AD pathogenesis, its precise role, whether aggravating or protective, is still being investigated.
Viral Infections
25-HC acts as an antiviral molecule, particularly against enveloped viruses. Its antiviral activity stems from its ability to disrupt cholesterol homeostasis and modify cellular membranes. It can reduce lipid rafts and cholesterol in the cell membrane by inhibiting cholesterol synthesis and promoting its efflux. This action prevents viral entry by blocking membrane fusion between the virus and the host cell.
25-HC has shown broad-spectrum antiviral activity against viruses such as SARS-CoV-2, HIV, Ebola virus, and Zika virus. For example, 25-HC inhibits the invasion of Zika virus and can alleviate associated inflammatory responses and viremia. The upregulation of CH25H and subsequent increase in 25-HC levels are part of the host’s innate immune response to viral infections.
Cancer
Emerging research indicates a potential role for 25-HC in cancer progression or suppression, although its effects can be complex and context-dependent. In some cancers, such as pancreatic ductal adenocarcinoma (PDAC), the loss of CH25H (the enzyme producing 25-HC) is associated with increased cholesterol accumulation, promoting cancer cell viability and accelerating tumor progression. Methylation of the CH25H gene and decreased expression levels have been observed in human pancreatic cancers, correlating with a less favorable prognosis.
Conversely, restoring CH25H expression in PDAC cells can decrease their viability and decelerate tumor growth. This suggests that 25-HC, through its influence on cholesterol and cellular processes, may have tumor-suppressive effects in this context. However, other studies suggest that 25-HC may activate signaling in breast and ovarian cancer cells, potentially contributing to their proliferation. This highlights the varied impact of 25-HC depending on the specific cancer type and cellular environment.