Our evolving understanding of how 27-hydroxycholesterol influences cancer

Ma, Liqian; Cho, Wonhwa; Nelson, Erik R.

doi:10.1016/j.bcp.2021.114621

Cited by 25 publications

(18 citation statements)

References 139 publications

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“…Our previous studies using cultured macrophages have also identified immunomodulatory effects caused by the inhibition of CES1. ,, For example, CES1 inactivation by either reactive pesticide metabolites or lentivirus-mediated knockdown resulted in an increase in cellular levels of endogenous 2-AG and PG-Gs due to the more limited degradation of these lipid mediators. , These bioactive lipids can modulate inflammation. − In addition, we showed that CES1 knockdown decreased the production of the oxysterol 27-hydroxycholesterol (27-OHC) in cholesterol-loaded macrophages, which was due to marked downregulation of the 27-OHC biosynthetic enzyme CYP27A1 . 27-OHC is another lipid mediator that exerts immune effects and is an endogenous ligand for LXRα . Furthermore, combined treatment of M1 polarized macrophages with WWL113 and PGD 2 -G attenuated IL-6 levels more strongly than that of PGD 2 -G alone, which suggested that blocking CES1 hydrolysis of PGD 2 -G potentiated the anti-inflammatory effect of this lipid mediator.…”

Section: Discussionmentioning

confidence: 88%

Carboxylesterase 1d Inactivation Augments Lung Inflammation in Mice

Szafran

Borazjani

Scheaffer

et al. 2022

ACS Pharmacol. Transl. Sci.

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Carboxylesterases are members of the serine hydrolase superfamily and metabolize drugs, pesticides, and lipids. Previous research showed that inhibition of carboxylesterase 1 (CES1) in human macrophages altered the immunomodulatory effects of lipid mediators called prostaglandin glyceryl esters, which are produced by cyclooxygenase-catalyzed oxygenation of the endocannabinoid 2-arachidonoylglycerol (2-AG). Ces1d − the mouse ortholog of human CES1 − is the most abundant Ces isoform in murine lung tissues and alveolar macrophages and a major target of organophosphate poisons. Monoacylglycerol lipase (Magl) is also expressed in murine lung and is the main enzyme responsible for 2-AG catabolism. Several metabolic benefits are observed in Ces1d −/− mice fed a high-fat diet; thus, we wondered whether pharmacological and genetic inactivation of Ces1d in vivo might also ameliorate the acute inflammatory response to lipopolysaccharide (LPS). C57BL/6 mice were treated with WWL229 (Ces1d inhibitor) or JZL184 (Magl inhibitor), followed 30 min later by either LPS or saline. Wild-type (WT) and Ces1d −/− mice were also administered LPS to determine the effect of Ces1d knockout. Mice were sacrificed at 6 and 24 h, and cytokines were assessed in serum, lung, liver, and adipose tissues. Lipid mediators were quantified in lung tissues, while activity-based protein profiling and enzyme assays determined the extent of lung serine hydrolase inactivation by the inhibitors. WWL229 was shown to augment LPS-induced lung inflammation in a female-specific manner, as measured by enhanced neutrophil infiltration and Il1b mRNA. The marked Ces inhibition in female lung by 4 h after drug treatment might explain this sex difference, although the degree of Ces inhibition in female and male lungs was similar at 6 h. In addition, induction of lung Il6 mRNA and prostaglandin E 2 by LPS was more pronounced in Ces1d −/− mice than in WT mice. Thus, WWL229 inhibited lung Ces1d activity and augmented the female lung innate immune response, an effect observed in part in Ces1d −/− mice and Ces1d/CES1-deficient murine and human macrophages. In contrast, JZL184 attenuated LPS-induced Il1b and Il6 mRNA levels in female lung, suggesting that Ces1d and Magl have opposing effects. Mapping the immunomodulatory molecules/pathways that are regulated by Ces1d in the context of lung inflammation will require further research.

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Section: Discussionmentioning

confidence: 88%

Carboxylesterase 1d Inactivation Augments Lung Inflammation in Mice

Szafran

Borazjani

Scheaffer

et al. 2022

ACS Pharmacol. Transl. Sci.

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“…27HC is an endogenous oxidized cholesterol synthesized by the liver and discovered as a selective modulator of the estrogen receptors (ERs) (44). The ERs are a key regulator of myriad physiological functions, playing a recognized or suggestive role in cancer progression in various cancer types, such as the breast, colorectal cancer and thyorid cancer (45). A previous study showed that cholesterol and 27HC could increase the aggressiveness of thyroid cancer (46).…”

Section: Discussionmentioning

confidence: 99%

Alterations of Gut Microbiome and Metabolite Profiles Associated With Anabatic Lipid Dysmetabolism in Thyroid Cancer

Gui

Jiang

et al. 2022

Front. Endocrinol.

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BackgroundCurrently, the high morbidity of individuals with thyroid cancer (TC) is an increasing health care burden worldwide. The aim of our study was to investigate the relationship among the gut microbiota community, metabolites, and the development of differentiated thyroid cancer.Methods16S rRNA gene sequencing and an integrated LC–MS-based metabolomics approach were performed to obtain the components and characteristics of fecal microbiota and metabolites from 50 patients with TC and 58 healthy controls (HCs).ResultsThe diversity and richness of the gut microbiota in the TC patients were markedly decreased. The composition of the gut microbiota was significantly altered, and the Bacteroides enterotype was the dominant enterotype in TC patients. Additionally, the diagnostic validity of the combined model (three genera and eight metabolites) and the metabolite model (six metabolites) were markedly higher than that of the microbial model (seven genera) for distinguishing TC patients from HCs. LEfSe analysis demonstrated that genera (g_Christensenellaceae_R-7_group, g_Eubacterium_coprostanoligenes_group) and metabolites [27-hydroxycholesterol (27HC), cholesterol] closely related to lipid metabolism were greatly reduced in the TC group. In addition, a clinical serum indicator (total cholesterol) and metabolites (27HC and cholesterol) had the strongest influence on the sample distribution. Furthermore, functional pathways related to steroid biosynthesis and lipid digestion were inhibited in the TC group. In the microbiota-metabolite network, 27HC was significantly related to metabolism-related microorganisms (g_Christensenellaceae_R-7_group).ConclusionsOur research explored the characteristics of the gut microecology of patients with TC. The findings of this study will help to discover risk factors that affect the occurrence and development of TC in the intestinal microecology.

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“…Cholesterol is metabolized to active derivatives, including cholesterol oxidation products (COP), called oxysterols, which have been shown to alter cell proliferation [ 46 , 47 ]. For example, a high concentration of 27-hydroxycholesterol (27HC), a kind of oxysterol, significantly increases the release of pro-inflammatory interleukins 6 and 8 and exerts tumor-promoting properties in colorectal cancer [ 48 , 49 ]. The ABCA5 gene assists in the transport of cellular cholesterol and is involved in the process of lipid metabolism [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of ABCA5 among ATP-Binding Cassette Transporter Family as a New Biomarker for Colorectal Cancer

Xiao

et al. 2022

Journal of Oncology

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Background. The increasing incidence and mortality of colorectal cancer (CRC) urgently requires updated biomarkers. The ABC transporter family is a widespread family of membrane-bound proteins involved in the transportation of substrates associated with ATP hydrolysis, including metabolites, amino acids, peptides and proteins, sterols and lipids, organic and inorganic ions, sugars, metals, and drugs. They play an important role in the maintenance of homeostasis in the body. Purpose. This study aims to search for new markers in the ABC transporter gene family for diagnostic and prognostic purposes through data mining of The Cancer Genome Atlas (TCGA) and GEO (Gene Expression Omnibus) datasets. Methods. A total of 980 samples, including 684 CRC patients and 296 controls from five different datasets, were included for analysis. The construction of the PPI (protein-protein interaction) network and pathway analysis were performed in STRING database and DAVID (database for annotation, visualization, and integrated discovery), respectively. In addition, GSEA (gene set enrichment analysis) and WGCNA (weighted gene co-expression network analysis) were also used for functional analysis. Results. After several rounds of screening and validation, only the ABCB5 gene was retained among the 49 genes. Conclusions. The results demonstrated that ABCA5 expression is reduced in CRC and patients with high ABCA5 expression have better OS, which can provide guidance for better management and treatment of CRC in the future.

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Our evolving understanding of how 27-hydroxycholesterol influences cancer

Cited by 25 publications

References 139 publications

Carboxylesterase 1d Inactivation Augments Lung Inflammation in Mice

Carboxylesterase 1d Inactivation Augments Lung Inflammation in Mice

Alterations of Gut Microbiome and Metabolite Profiles Associated With Anabatic Lipid Dysmetabolism in Thyroid Cancer

Identification of ABCA5 among ATP-Binding Cassette Transporter Family as a New Biomarker for Colorectal Cancer

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