25-Hydroxycholesterol as a Signaling Molecule of the Nervous System

Abstract

Cholesterol is an essential component of plasma membrane and precursor of biological active compounds, including hydroxycholesterols (HCs). HCs regulate cellular homeostasis of cholesterol; they can pass across the membrane and vascular barriers and act distantly as para-and endocrine agents. A small amount of 25-hydroxycholesterol (25-HC) is produced in the endoplasmic reticulum of most cells, where it serves as a potent regulator of the synthesis, intracellular transport, and storage of cholesterol. Production of 25-HC is strongly increased in the macrophages, dendrite cells, and microglia at the infl ammatory response. The synthesis of 25-HC can be also upregulated in some neurological disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, spastic paraplegia type 5, and X-linked adrenoleukodystrophy. However, it is unclear whether 25-HC aggravates these pathologies or has the protective properties. The molecular targets for 25-HC are transcriptional factors (LX receptors, SREBP2, ROR), G protein-coupled receptor (GPR183), ion channels (NMDA receptors, SLO1), adhesive molecules (α5β1 and ανβ3 integrins), and oxysterol-binding proteins. The diversity of 25-HC-binding proteins points to the ability of HC to aff ect many physiological and pathological processes. In this review, we focused on the regulation of 25-HC production and its universal role in the control of cellular cholesterol homeostasis, as well as the eff ects of 25-HC as a signaling molecule mediating the infl uence of infl ammation on the processes in the neuromuscular system and brain. Based on the evidence collected, it can be suggested that 25-HC prevents accumulation of cellular cholesterol and serves as a potent modulator of neuroinfl ammation, synaptic transmission, and myelinization. An increased production of 25-HC in response to a various type of damage can have a protective role and reduce neuronal loss. At the same time, an excess of 25-HC may exert the neurotoxic eff ects.

25-Hydroxycholesterol and 27-hydroxycholesterol induce neuroinflammation by activating microglia

“…It is converted to 7α-hydroxy-3-oxo-4-cholestenoic acid, which ows from the brain into the circulation via reactions catalyzed by 25-hydroxycholesterol 7-alpha-hydroxylase (CYP7B1) and 3 beta-hydroxysteroid dehydrogenase type 7 (HSD3B7) [32]. 25OHChol, which is mainly produced by macrophages including microglia, reduces cholesterol synthesis in astrocytes [33]. We demonstrated differential effects of side-chain oxysterols on microglial activation and IL-1β expression.…”

A unified model of the biology of peripartum depression

“…Maternal stress also influences circulating levels of inflammatory markers by increasing pro-inflammatory cytokines IL-1β, IL-6, and tumor necrosis factor α (TNF-α); an increase in pro-inflammatory factors upregulates the IDO enzyme expression that further intensifies kynurenine metabolism [ 25 ]. Third, glucocorticoid receptors also inhibit the function of important neurosteroids, such as 25-hydroxycholesterol (a cholestane) [ 54 ], which typically suppresses the activation of glutamate’s NMDA receptor [ 55 ]. By doing so, the stress response further intensifies the negative effects of QUIN on the NMDA receptor by blocking essential inhibitors of the process.…”

Is reverse cholesterol transport regulated by active cholesterol?

“…Presumably, one of these responses is the production of 25-HC, another important homeostatic effector ( 37 , 45 ). It has been argued that 25-HC, like 27HC, stimulates the expression of the proteins that mediate reverse cholesterol transport ( 46 ). However, this inference is not secure ( 37 , 47 ).…”