25-Hydroxycholesterol activates the expression of cholesterol 25-hydroxylase in an LXR-dependent mechanism

Liu, Ying; Zhuo, Wei; Ma, Xingzhe; Yang, Xiaoxiao; Chen, Yuanli; Sun, Lei; Ma, Chuanrui; Miao, Qing; Hajjar, David P.; Han, Jihong; Duan, Yajun

doi:10.1194/jlr.m080440

Cited by 63 publications

(56 citation statements)

References 32 publications

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“…In addition, CH25H is an IFN-inducible molecule (4,5). Interestingly, we have reported that expression of hepatic CH25H or macrophage IFN- can be activated by LXR (15,16). Based on the above studies, we hypothesized that LXR activation may play an important role in antiviral infection by activating CH25H expression.…”

Section: Lxr Activation Inhibits Infection Of Hsv-1 or Mlv-(vsv)-gfp mentioning

confidence: 95%

“…After treatment, cellular proteins were extracted. Expression of CH25H, LXR, LXR, IFN-, SULT2B1b protein, and total HSV-1 proteins in cellular lysate was determined by Western blot as described (15). Expression of GAPDH or -tubulin was determined as loading control.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Previously, we identified several LXR response elements in the CH25H promoter, and found that both 25HC and synthetic LXR ligand [T0901317 (T317) or GW3965] induced CH25H expression in different cell types. Furthermore, treatment of mice with GW3965 increased CH25H expression in liver and peritoneal macrophages (15).…”

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confidence: 95%

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Activation of liver X receptor plays a central role in antiviral actions of 25-hydroxycholesterol

Liu

Zhuo

Zhang

et al. 2018

Journal of Lipid Research

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25-Hydroxycholesterol (25HC) is produced in cells by an enzymatic reaction catalyzed by cholesterol 25-hydroxylase (CH25H). 25HC can function as an inhibitor of viral infection and an endogenous agonist of liver X receptor (LXR), a ligand-activated transcription factor. The previous studies have demonstrated the multiple biological functions of 25HC. For instance, CH25H expression and 25HC production are involved in immunological processes (1). Stimulation of macrophage Toll-like receptors can induce CH25H expression and consequently enhance 25HC production/ secretion and suppress immunoglobulin A production (2). CH25H expression in bone marrow-derived dendritic cells and macrophages can be upregulated by interferons (IFNs) (3). This finding results in the identification of CH25H as one of the IFN-stimulated genes and 25HC as a potent inhibitor of viral infection (4, 5). In vitro, 25HC can inhibit growth of multiple viruses in cells by blocking viral entry. The inhibition of viral infection by IFNs is also related to induction of CH25H expression and 25HC production (4, 5). In vivo, CH25H-deficient mice are more susceptible to viral infection than wild-type mice (4). 25HC also functions as an amplifier of inflammatory signaling via the activator protein 1 signaling pathway (6) and mediates the negative-feedback pathway of IFN signaling on interleukin 1 family cytokine production and inflammasome activity (7). Besides antiviral infection (4, 5, 8-11), 25HC can regulate lipid/cholesterol metabolism by interacting with sterol regulatory element-binding proteins or LXR (12). LXR plays various biological roles, particularly in lipid metabolism Abstract Production of 25-hydroxycholesterol (25HC), a potent inhibitor of viral infection, is catalyzed by cholesterol 25-hydroxylase (CH25H). We previously reported that 25HC induced CH25H expression in a liver X receptor (LXR)dependent manner, implying that LXR can play an important role in antiviral infection. In this study, we determined that activation of LXR by 25HC or synthetic ligands [T0901317 (T317) or GW3965] inhibited infection of herpes simplex virus type 1 (HSV-1) or MLV-(VSV)-GFP in HepG2 cells or RAW 264.7 macrophages. Genetic deletion of LXR, LXR, or CH25H expression in HepG2 cells by CRISPR/Cas9 method increased cell susceptibility to HSV-1 infection and attenuated the inhibition of LXR on viral infection. Lack of interferon (IFN)- expression also increased cell susceptibility to viral infection. However, it attenuated, but did not block, the inhibition of LXR on HSV-1 infection. In addition, expression of CH25H, but not IFN-, was inversely correlated to cell susceptibility to viral infection and the antiviral actions of LXR. Metabolism of 25HC into 25HC-3-sulfate (25HC3S) by cholesterol sulfotransferase-2B1b moderately reduced the antiviral actions of 25HC because 25HC3S is a weaker inhibitor of HSV-1 infection than 25HC. Furthermore, administration of T317 to BALB/c mice reduced HSV-1 growth in mouse tissues. Taken together, we demonstrate an antiviral s...

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Section: Lxr Activation Inhibits Infection Of Hsv-1 or Mlv-(vsv)-gfp mentioning

confidence: 95%

Section: Western Blot Analysismentioning

confidence: 99%

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Activation of liver X receptor plays a central role in antiviral actions of 25-hydroxycholesterol

Liu

Zhuo

Zhang

et al. 2018

Journal of Lipid Research

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“…Recently, Liu et al. reported that 25‐HC induces expression of CH25H via activation of LXR . Hence, a widely used potent LXR agonist, TO901317 was used to explore whether it could lower VLCFA levels.…”

Section: Figurementioning

confidence: 99%

“…[21] Recently, Liu et al reported that 25-HC induces expression of CH25H via activation of LXR. [22] Hence, a widely used potent LXR agonist, TO901317 was used to explore whether it could lower VLCFA levels. As shown in Figure 5, TO901317 significantly reduced VLCFA levels in CCALD and AMN fibroblasts.…”

Section: Exogenous Addition Of 25-hydroxycholesterol Reduces Level Ofmentioning

confidence: 99%

Exogenous Addition of 25‐Hydroxycholesterol Reduces Level of Very Long‐Chain Fatty Acids in X‐Linked Adrenoleukodystrophy

et al. 2019

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X‐Linked adrenoleukodystrophy (X‐ALD) is a severe metabolic disorder characterized by the accumulation of very long‐chain fatty acids (VLCFAs). Recently, we demonstrated that levels of 25‐hydroxycholesterol (25‐HC) and cholesterol 25‐hydroxylase (CH25H) were found to be elevated in X‐ALD. Herein, we report that the exogenous addition of 25‐HC significantly reduces C26:0 levels in X‐ALD patient‐derived fibroblasts and oligodendrocytes differentiated from induced pluripotent stem cells (iPSCs) derived from X‐ALD patients. Moreover, 25‐HC treatment was found to down‐regulate the expression of ELOVL1, a key enzyme for the synthesis of C26. In addition, activation of liver X receptor (LXR), a molecular target of endogenous 25‐HC, also reduced C26:0 level. The reduction of C26:0 levels by 25‐HC treatment might result, at least partially, from the decrease of ELOVL1 expression as well as the activation of LXR. Our findings could provide a better understanding of the role of 25‐HC in X‐ALD and useful information to find therapeutic agents to treat X‐ALD.

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Platycodin D inhibits autophagy and increases glioblastoma cell death via LDLR upregulation

et al. 2021

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Targeting autophagy is a promising therapeutic approach in cancer therapy. Here, we screened 30 traditional herbal medicines to identify novel autophagy regulators and found that Platycodon grandiflorus (PG) and platycodin D (PD), a triterpenoid saponin from PG, inhibited autophagy in glioblastoma multiforme (GBM) cells. Mechanistically, PD prevented lysosomal degradation and the fusion between autophagosomes and lysosomes by inducing sequestration of free cholesterol in lysosomes. The autophagy inhibitory effect of PD was mimicked by both genetic and pharmacological inhibition of Niemann-Pick C1 (NPC1), which exports lowdensity lipoprotein (LDL)-derived cholesterol from lysosomes. Moreover, PD promoted the uptake of exogenous LDL cholesterol via upregulation of LDL receptor (LDLR), leading to further accumulation of cholesterol within lysosomes and GBM cell death. Importantly, these phenomena were more pronounced in LDLR-overexpressing GBM cells than in normal astrocytes. Finally, blockade of cholesterol uptake by LDLR knockdown reversed the PD-induced inhibition of autophagy and GBM cell growth. Our study proposes that PD could be a potent anti-GBM drug by disrupting cholesterol trafficking and autophagy.

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25-Hydroxycholesterol activates the expression of cholesterol 25-hydroxylase in an LXR-dependent mechanism

Cited by 63 publications

References 32 publications

Activation of liver X receptor plays a central role in antiviral actions of 25-hydroxycholesterol

Activation of liver X receptor plays a central role in antiviral actions of 25-hydroxycholesterol

Exogenous Addition of 25‐Hydroxycholesterol Reduces Level of Very Long‐Chain Fatty Acids in X‐Linked Adrenoleukodystrophy

Platycodin D inhibits autophagy and increases glioblastoma cell death via LDLR upregulation

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