[Back to Issue 6 ToC] [Back to Journal Contents] [Back to Biochemistry (Moscow) Home page]

REVIEW: 25-Hydroxycholesterol as a Signaling Molecule of the Nervous System

Ulia G. Odnoshivkina1,2#, Eva A. Kuznetsova1#, and Alexey M. Petrov1,2,a*

1Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, Federal Research Center “Kazan Scientific Center of Russian Academy of Sciences”, 420111 Kazan, Russia

2Kazan State Medical University, 420012 Kazan, Russia

# These authors contributed equally to this work.

* To whom correspondence should be addressed.

Received March 25, 2022; Revised May 10, 2022; Accepted May 10, 2022
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 inflammatory 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 affect 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 effects of 25-HC as a signaling molecule mediating the influence of inflammation 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 neuroinflammation, 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 effects.
KEY WORDS: cholesterol, 25-hydroxycholesterol, liver X receptors, NMDA receptors, synaptic transmission, neuroinflammation, microglia

DOI: 10.1134/S0006297922060049