Multifaceted Functions of CH25H and 25HC to Modulate the Lipid Metabolism, Immune Responses, and Broadly Antiviral Activities

Abstract

<jats:p>With the frequent outbreaks of emerging infectious diseases in recent years, an effective broad-spectrum antiviral drug is becoming an urgent need for global public health. Cholesterol-25-hydroxylase (CH25H) and its enzymatic products 25-hydroxycholesterol (25HC), a well-known oxysterol that regulates lipid metabolism, have been reported to play multiple functions in modulating cholesterol homeostasis, inflammation, and immune responses. CH25H and 25HC were recently identified as exerting broadly antiviral activities, including upon a variety of highly pathogenic viruses such as human immunodeficiency virus (HIV), Ebola virus (EBOV), Nipah virus (NiV), Rift Valley fever virus (RVFV), and Zika virus (ZIKV). The underlying mechanisms for its antiviral activities are being extensively investigated but have not yet been fully clarified. In this study, we summarized the current findings on how CH25H and 25HC play multiple roles to modulate cholesterol metabolism, inflammation, immunity, and antiviral infections. Overall, 25HC should be further studied as a potential therapeutic agent to control emerging infectious diseases in the future.</jats:p>

Mammalian and Avian Host Cell Influenza A Restriction Factors

“…Shortly, CH25H and 25HC inhibit the transcription factor sterol regulatory element-binding protein (SREBP) and activate the transcription factor liver X receptor (LXR). These two transcriptional factors have a great importance in modulating cellular cholesterol homeostasis [ 157 ]. Moreover, 25HC also represses the expression of the HMGCR gene and induces the degradation of the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) protein, which leads to an inhibition of the cholesterol biosynthesis pathway.…”

“…Moreover, 25HC also represses the expression of the HMGCR gene and induces the degradation of the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) protein, which leads to an inhibition of the cholesterol biosynthesis pathway. CH25H and its product 25HC have been shown to be involved in the restriction of a large number of enveloped viruses by inhibiting the fusion between viral and endosomal membranes [ 157 ]. This antiviral activity was also observed in vitro for IAV both in canine MDCK cells (i.e., the cell line typically used for IAV amplification in vitro ) [ 158 ] and in murine immortalized airway epithelial cells [ 159 ], suggesting that CH25H is a restriction factor for IAV.…”

Diverse Immunoregulatory Roles of Oxysterols—The Oxidized Cholesterol Metabolites

“…Ch25h is an interferon-inducible gene and 25-HC has some well described protective roles in viral infection. 25-HC inhibits viral entry into cells, interferes with viral genome replication and with viral replication and assembly (see [ 1 ] for review). 25-HC has been shown to be broadly anti-viral and inhibits the infection of numerous viruses including HCV, HIV, Zika virus and Reovirus [ 55 , 147 , 148 , 149 ].…”

“…Cholesterol can be obtained from our diet or synthesised within individual cells and the control of cholesterol homeostasis is carefully regulated. Indeed, elevated overall cholesterol and products of cholesterol metabolism such as oxysterols have been implicated in infection [ 1 ] and several diseases such as atherosclerosis, cancer, neurodegeneration and more [ 2 , 3 , 4 , 5 , 6 ]. It is becoming clear that oxysterols can have important regulatory roles within cells and between cells and how oxysterols control the immune system is the focus of this current review.…”

Multiple Roles of 25-Hydroxycholesterol in Lipid Metabolism, Antivirus Process, Inflammatory Response, and Cell Survival

“…Oxysterols link the bridge between lipid metabolism and innate and adaptive immune response [ 61 ]. As an ISG, Ch25h is highly induced in virus infection, and 25-HC is impressive for its potent ability to inhibit virus invasion through a strand of mechanisms [ 62 ].…”