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CHOLESTEROL 25-HYDROXYLASE; CH25H

CHOLESTEROL 25-HYDROXYLASE; CH25H

HGNC Approved Gene Symbol: CH25HCytogenetic location: 10q23.31 Genomic coordinates (GRCh38): 10:89,205,628-89,207,316 (from NCBI)▼ DescriptionCH25H is an int...

HGNC Approved Gene Symbol: CH25H

Cytogenetic location: 10q23.31 Genomic coordinates (GRCh38): 10:89,205,628-89,207,316 (from NCBI)

▼ Description
CH25H is an interferon (IFN)-stimulated gene than encodes an endoplasmic reticulum (ER)-associated enzyme that converts cholesterol to 25-hydroxycholesterol (25HC). The soluble factor 25HC controls sterol biosynthesis through regulation of sterol-responsive element-binding proteins (see 184756) and nuclear receptors. In addition, 25HC has broad antiviral activity (summary by Liu et al., 2013).

▼ Cloning and Expression
Oxysterols regulate the expression of genes involved in cholesterol and lipid metabolism. By screening pools of murine hepatic cDNAs for the ability to convert cholesterol to oxysterols, Lund et al. (1998) cloned mouse cholesterol 25-hydroxylase. They isolated the human CH25H cDNA by hybridization screening of a lung cDNA library using an EST sequence with homology to the mouse enzyme sequence. The deduced 272-amino acid peptide has characteristics of a polytopic membrane protein and contains clusters of histidine residues essential for catalytic activity. Northern blot analysis showed very low levels of cholesterol 25-hydroxylase mRNA in 16 different tissues. Immunohistochemistry detected cholesterol 25-hydroxylase in the ER and a perinuclear compartment of transfected cells.

▼ Gene Structure
Lund et al. (1998) isolated a genomic cholesterol 25-hydroxylase clone and showed that the CH25H gene lacks introns.

▼ Mapping
By fluorescence in situ hybridization and by somatic and radiation hybrid DNA panel mapping, Lund et al. (1998) mapped the CH25H gene to chromosome 10q23.

▼ Gene Function
Using mouse and human cells, Liu et al. (2013) showed that CH25H had broad antiviral activity against acutely pathogenic viruses, such as Ebola virus, Rift Valley fever virus, Nipah virus, and Russian spring-summer encephalitis virus, and against chronic persistent viruses, such as human immunodeficiency virus (HIV)-1, herpes simplex virus, vesicular stomatitis virus, and murine gammaherpes virus (MHV68). Virus growth was suppressed by blocking membrane fusion between virus and cell. Liu et al. (2013) concluded that 25HC plays a beneficial role in promoting host immunity against viral infections.

Using quantitative metabolome profiling of naturally occurring oxysterols in mice upon infection or IFN stimulation, Blanc et al. (2013) identified 25HC as the only macrophage-synthesized and -secreted oxysterol. Ifnb (147640) was the primary mediator of macrophage production of 25HC, and Stat1 (600555) was also required. Chromatin immunoprecipitation analysis showed that Stat1 bound the Ch25h promoter. Blanc et al. (2013) concluded that CH25H activation is coupled to the IFN response through a direct molecular link with STAT1.

Choi et al. (2019) showed that the CH25H-CYP7B1 (603711)-ROR-alpha (600825) axis of cholesterol metabolism in chondrocytes is a crucial catabolic regulator of the pathogenesis of osteoarthritis. They found that mouse osteoarthritic chondrocytes had increased levels of cholesterol because of enhanced uptake, upregulation of cholesterol hydroxylases (CH25H and CYP7B1), and increased production of oxysterol metabolites. Adenoviral overexpression of CH25H or CYP7B1 in mouse joint tissues caused experimental osteoarthritis, whereas knockout or knockdown of these hydroxylases abrogated the pathogenesis of osteoarthritis. Moreover, ROR-alpha was found to mediate the induction of osteoarthritis by alterations in cholesterol metabolism. Choi et al. (2019) concluded that their results indicated that osteoarthritis is a disease associated with metabolic disorders and suggested that targeting the CH25H-CYP7B1-ROR-alpha axis of cholesterol metabolism may provide a therapeutic avenue for treating osteoarthritis.

▼ Animal Model
Liu et al. (2013) found that mice lacking Ch25h were more susceptible than wildtype mice to lytic infection with MHV68. Administration of 25HC to humanized mice suppressed HIV replication and reversed T-cell depletion.

Reboldi et al. (2014) found that activated mouse macrophages lacking Ch25h were unable to produce Il1 family cytokines, such as Il1b (147720), but were able to produce Il6 (147620) or Il23 (605580). Mice lacking Ch25h had increased numbers of Il17a (603149)-positive cells in spleen and lymph nodes and increased circulating neutrophils, whereas mice lacking Gpr183 (605741), a receptor for a downstream product of Ch25h, did not show these effects. RNA sequence analysis of Ch25h-null macrophages revealed a striking elevation in transcripts of Srebp target genes. Reboldi et al. (2014) noted that 25HC antagonizes processing of SREBP1 (SREBF1; 184756) and SREBP2 (SREBF2; 600481) by promoting their INSIG (602055)-mediated retention in the ER, and they showed that repression of SREBP processing contributed to 25HC-mediated downregulation of Il1b and inflammasome activity. Mice lacking Ch25h underwent exacerbated experimental autoimmune encephalitis, but they showed more resistance to Listeria growth, accompanied by elevated serum Il1b, Il1a (147760), and Il18 (600953). Reboldi et al. (2014) concluded that CH25H and 25HC play essential roles in the negative-feedback mechanism regulating IL1 family cytokine production during type I IFN inflammatory conditions by repressing IL1B expression and inflammasome activity.

Tags: 10q23.31