Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage

Wang, Yaping; Li, Xiaobo

doi:10.3390/metabo11010009

Cited by 25 publications

(22 citation statements)

References 86 publications

(148 reference statements)

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“…They decrease lipid biosynthesis, suppress inflammatory responses, and promote cell survival by acting through epigenetic modification. 130,131 The intravenous administration of one of these oxysterol sulfates, DUR-928, has been evaluated in a pivotal, phase IIA, open-label study enrolling 19 patients with moderate-severe acute alcoholic hepatitis. Based on promising safety and efficacy signals, 132,133 phase IIB studies have now been planned (ClinicalTrials.gov identifiers: NCT03917407 and NCT04563026).…”

Section: Key Pointmentioning

confidence: 99%

The search for disease-modifying agents in decompensated cirrhosis: From drug repurposing to drug discovery

Caraceni

Abraldes

Ginès

et al. 2021

Journal of Hepatology

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Patients with decompensated cirrhosis are currently managed through targeted strategies aimed at preventing or treating specific complications. In contrast, a disease-modifying agent should, by definition, be aimed at globally addressing 'decompensated cirrhosis'. To be defined as a disease-modifying agent in decompensated cirrhosis, interventions need to demonstrate an unequivocal benefit on the course of disease in well-designed and adequately powered randomised clinical trials with hard endpoints (i.e. patient survival). These trials also need to define the target population, dosage and timing of administration, factors guiding treatment, temporary or permanent stopping rules, transferability to daily clinical practice, cost-effectiveness, and global treatment access. By eliminating the underlying cause of cirrhosis, aetiologic treatments can still influence the course of decompensated disease by halting or slowing down disease progression or even inducing reversion to the compensated state. In contrast, there remains an unmet clinical need for disease-modifying agents which can antagonise key pathophysiological mechanisms of decompensated cirrhosis, such as portal hypertension, gut translocation, circulatory dysfunction, systemic inflammation, and immunological dysfunction. However, in the last few years, the repurposing of "old drugs" that have already been prescribed for more limited indications in hepatology or for other diseases has provided a few candidates, including human albumin, statins, and poorly absorbable oral antibiotics, which are under further evaluation in large-scale randomised clinical trials. New disease-modifying agents are also expected to be identified in the next decade through the systematic repurposing of existing drugs and the development of novel molecules which are currently undergoing pre-clinical or early clinical testing.

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Section: Key Pointmentioning

confidence: 99%

The search for disease-modifying agents in decompensated cirrhosis: From drug repurposing to drug discovery

Caraceni

Abraldes

Ginès

et al. 2021

Journal of Hepatology

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“…In addition, 25-HC can be sulfated at its 3-position by sulfotransferase 2B1b to generate 25-HC3S, which can be further sulfated by sulfotransferase 2A1 [29]. In contrast to 25-HC, 25-HC3S is a potent antagonist of DMNT-1, -3a and -3b, and opposes its actions on target genes [27,30,31]. In a lipopolysaccharide-induced model of acute lung injury, 25-OHC concentrations are elevated, potentially promoting inflammation and the recruitment of leukocytes [32].…”

Section: Introductionmentioning

confidence: 99%

“…In a lipopolysaccharide-induced model of acute lung injury, 25-OHC concentrations are elevated, potentially promoting inflammation and the recruitment of leukocytes [32]. Since 25-HC3S has beneficial effects in models of non-alcoholic fatty liver disease, organ damage and inflammation, and has been evaluated favourably in clinical trials, further elucidation of the roles of this oxysterol metabolite in the regulation of immune cells will be of great value [31].…”

Section: Introductionmentioning

confidence: 99%

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Multiple Targets for Oxysterols in Their Regulation of the Immune System

Reinmuth

Hsiao

Hamann

et al. 2021

Cells

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Oxysterols, or cholesterol oxidation products, are naturally occurring lipids which regulate the physiology of cells, including those of the immune system. In contrast to effects that are mediated through nuclear receptors or by epigenetic mechanism, which take tens of minutes to occur, changes in the activities of cell-surface receptors caused by oxysterols can be extremely rapid, often taking place within subsecond timescales. Such cell-surface receptor effects of oxysterols allow for the regulation of fast cellular processes, such as motility, secretion and endocytosis. These cellular processes play critical roles in both the innate and adaptive immune systems. This review will survey the two broad classes of cell-surface receptors for oxysterols (G-protein coupled receptors (GPCRs) and ion channels), the mechanisms by which cholesterol oxidation products act on them, and their presence and functions in the different cell types of the immune system. Overall, this review will highlight the potential of oxysterols, synthetic derivatives and their receptors for physiological and therapeutic modulation of the immune system.

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“…The potent regulatory oxysterol sulfate, 25-hydroxy cholesterol 3-sulfate (25HC3S; 5-cholesten-3β,25-diol 3sulfate), has been reported to play important roles in lipid metabolism, inflammatory responses, and cell survival since its discovery in hepatocyte nuclei (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Although some other sterol sulfates have been discovered and shown to be important cell regulatory metabolites [cholesterol sulfate, 27-hydroxycholesterol 3-sulfate (27HC3S), 27HCDS, and 25HCDS] (19-22), 25HC3S appears to be the most potent regulator and has been used as a biomedicine for therapy of acute and chronic diseases, which are at phase II clinical trials (DUR928 represents 25HC3S; www.durect.com).…”

mentioning

confidence: 99%

25-Hydroxycholesterol 3-sulfate is an endogenous ligand of DNA methyltransferases in hepatocytes

Wang

Lin

Brown

et al. 2021

Journal of Lipid Research

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The oxysterol sulfate, 25-hydroxycholesterol 3-sulfate (25HC3S), has been shown to play an important role in lipid metabolism, inflammatory response, and cell survival. However, the mechanism(s) of its function in global regulation is unknown. The current study investigates the molecular mechanism by which 25HC3S functions as an endogenous epigenetic regulator. To study the effects of oxysterols/sterol sulfates on epigenetic modulators, 12 recombinant epigenetic enzymes were used to determine whether 25HC3S acts as their endogenous ligand. The enzyme kinetic study demonstrated that 25HC3S specifically inhibited DNA methyltransferases (DNMTs), DNMT1, DNMT3a, and DNMT3b with IC 50 of 4.04, 3.03, and 9.05 × 10 −6 M, respectively. In human hepatocytes, high glucose induces lipid accumulation by increasing promoter CpG methylation of key genes involved in development of nonalcoholic fatty liver diseases. Using this model, whole genome bisulfate sequencing analysis demonstrated that 25HC3S converts the 5m CpG to CpG in the promoter regions of 1,074 genes. In addition, we observed increased expression of the demethylated genes, which are involved in the master signaling pathways, including MAPK-ERK, calcium-AMP-activated protein kinase, and type II diabetes mellitus pathways. mRNA array analysis showed that the upregulated genes encoded for key elements of cell survival; conversely, downregulated genes encoded for key enzymes that decrease lipid biosynthesis. Taken together, our results indicate that the expression of these key elements and enzymes are regulated by the demethylated signaling pathways. We summarized that 25HC3S DNA demethylation of 5m CpG in promoter regions is a potent regulatory mechanism.

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Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage

Cited by 25 publications

References 86 publications

The search for disease-modifying agents in decompensated cirrhosis: From drug repurposing to drug discovery

The search for disease-modifying agents in decompensated cirrhosis: From drug repurposing to drug discovery

Multiple Targets for Oxysterols in Their Regulation of the Immune System

25-Hydroxycholesterol 3-sulfate is an endogenous ligand of DNA methyltransferases in hepatocytes

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