25-Hydroxycholesterol in health and diseases

Abstract

Cholesterol is an essential structural component of all membranes of mammalian cells where it plays a fundamental role not only in cellular architecture, but also, for example, in signaling pathway transduction, endocytosis process, receptor functioning and recycling, or cytoskeleton remodeling. Consequently, intracellular cholesterol concentrations are tightly regulated by complex processes, including cholesterol synthesis, uptake from circulating lipoproteins, lipid transfer to these lipoproteins, esterification, and metabolization into oxysterols that are intermediates for bile acids. Oxysterols have been considered for long time as sterol waste products, but a large body of evidence has clearly demonstrated that they play key roles in central nervous system functioning, immune cell response, cell death, or migration and are involved in age-related diseases, cancers, autoimmunity, or neurological disorders. Among all the existing oxysterols, this review summarizes basic as well as recent knowledge on 25-hydroxycholesterol which is mainly produced during inflammatory or infectious situations and that in turn contributes to immune response, central nervous system disorders, atherosclerosis, macular degeneration, or cancer development. Effects of its metabolite 7α,25-dihydroxycholesterol are also presented and discussed.

Keywords: 25-hydroxycholesterol; 7α,25-dihydroxycholesterol; ABCA1; LXR; cholesterol; oxysterols; reverse cholesterol transfer.

Fig. 1

Regulation of intracellular cholesterol pools. Circulating low-density lipoproteins (LDL) are recognized and internalized by LDL receptor (LDLR) expressed at the cell plasma membrane (PM). It starts the endocytosis process that leads to transfer the cholesterol to late endosomes and subsequently to the lysosomes. Cholesterol is then transferred to the PM where it participates to membrane fluidity, signaling processes, etc. Excess of PM cholesterol is transferred to high density lipoproteins (HDL) by the transporter ABCA1 through the reverse cholesterol transfer (RCT) process. ABCA1 can also flip cholesterol from the inner PM sheath to the outer sheath. Excess of cholesterol might be also metabolized into oxysterols with many of them that are ligands for the liver X Receptor (LXR) pathway. Activation of LXR by oxysterols increase ABCA1 expression and then cholesterol release to HDL. If the PM cholesterol content remains elevated, cholesterol is transferred to the endoplasmic reticulum (ER) by Aster proteins. This triggers the trapping of the SREBP cleavage–activating protein (SCAP)/sterol response element–binding protein 2 (SREBP-2) complex within the ER that it abolishes the transcriptional expression of LDLR and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme responsible for cholesterol synthesis. ABCA1, ATP-binding cassette subfamily A member 1.

Fig. 2

Production and roles of 25-hydroxycholesterol and 7α,25-dihydroxycholesterol. 25-hydroxylase (CH25H) converts cholesterol into 25-hydroxycholesterol (25-HC), which is then converted into 7α,25-dihydroxycholesterol (7α,25-DHC) by cytochrome P450 family 7 subfamily B member 1 (CYP7B1). 25-HC can also be provided by the diet. Many studies report effects of 25-HC and 7α,25-DHC in several cellular processes thus underlying their involvement in atherosclerosis, in cancers onset and development, immune response, and in neurodegenerative disorders.

Fig. 3

Expression patterns of CH25H and CYP7B1 transcripts in different organs and in males and females. These data were obtained from Human Protein Atlas Website consulted in September 26th 2023. Consensus transcript expression levels summarized per gene in 50 tissues based on transcriptomics data Human Protein Atlas RNA-seq and The Genotype-Tissue Expression project. The consensus normalized expression (“nTPM”) value is calculated as the maximum nTPM value for each gene in the two data sources. For tissues with multiple subtissues (brain regions, lymphoid tissues, and intestine) the maximum of all subtissues is used for the tissue type. The tab-separated file includes Ensembl gene identifier (“Gene”), analyzed sample (“Tissue”) and normalized expression (“nTPM”). The data is based on The Human Protein Atlas version 23.0 and Ensembl version 109 (56).

Fig. 4

Molecular mechanisms of 25-HC protection against virus infection. 25-HC plays a key role by restricting virus fusion with the plasma membrane (PM) and entrance within cells. Several molecular mechanisms have been reported. The first molecular mechanism decreases PM cholesterol composition and consists to activate the LXR signaling pathway, and then the ABCA1-mediated cholesterol efflux (1). 25-HC also depletes this accessible cholesterol of the PM by activating the ACAT. This enzyme is located into the endoplasmic reticulum (ER) and esterifies cholesterol. Esterified cholesterol is then stored in cytosolic lipid droplets that decrease ER cholesterol that is then replaced by cholesterol transferred from PM (2). The third mechanism consists of sequestration of SREBP-2 into the ER via interacting with INSIG1/2 and SCAP, thus blocking SREBP-2 cleavage and the subsequent transcription of HMGCR and LDLR (3). 25-HC also promotes HMGCR interaction with INSIG1/2 that it leads to its ubiquitinylation by the E3 ubiquitin ligase autocrine motility factor receptor (AMFR) and proteosomal degradation (3′). Then, 25-HC modulates activity of cellular mediators like oxysterol-binding protein (OSBP) and the vesicle-associated membrane protein-associated protein-A (VAP-A), that provokes disturbances in the recycling of cholesterol between the ER and the late endosomes with the consequence to block the viral particles inside these vesicles, and do not allow their replications in the cytosol (4). Lastly, it has been recently reported that 25-HC down-regulates the junction adhesion molecule-A (JAM-A) and the cation independent isoform of mannose-6-phosphate receptor (M6PR), two crucial molecules essential for infection of a variety of viruses (5). 25-HC, 25-hydroxycholesterol; ABCA1, ATP-binding cassette transporter subfamily A member 1; ACAT, acetyl-CoA acetyltransferase; HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; INSIG, insulin-induced gene; LDLR, low density lipoprotein receptor; LXR, liver X receptor; SREBP-2, sterol response element binding protein 2.