Controlled bile acid exposure to oesophageal mucosa causes up-regulation of nuclear γ-H2AX possibly via iNOS induction

Jiang, Bo; Zhao, Shengqian; Tao, Zhen; Wen, Jin Fu; Yang, Yancheng; Zheng, Yin; Yan, Hong-Ling; Sheng, Ying; Gao, Aimin

doi:10.1042/bsr20160124

Cited by 7 publications

(15 citation statements)

References 25 publications

(21 reference statements)

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“…The chemotherapy agent camptothecin (CPT) served as assay positive control. As expected, based on previous reports, 32 , 33 treatment with BAC at pH4 increased both the average number of foci per cell (Figure 8F ), as well as the number of cells with greater than 5 foci (Figure 8G ). Blocking FADS2 with SC26196 decreased γH2AX foci in both baseline and BAC treated cells (Figure 8F,G ).…”

Section: Resultssupporting

confidence: 91%

“…The double bonds in polyunsaturated lipids are susceptible to attack by ROS, which is increased in most cancers 36 . In EAC, bile acids in combination with low pH consistent with GERD induce genotoxic oxidative stress 7,32,33 . Here, we report FADS2 inhibition protects against bile acid‐induced DNA damage, concomitant with a reduction in polyunsaturated lipids with 4 or more double bonds, and a change in some lipid classes.…”

Section: Discussionmentioning

confidence: 60%

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Elevation of fatty acid desaturase 2 in esophageal adenocarcinoma increases polyunsaturated lipids and may exacerbate bile acid‐induced DNA damage

Molendijk

Kolka

Cairns

et al. 2022

Clinical & Translational Med

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Background The risk of esophageal adenocarcinoma (EAC) is associated with gastro‐esophageal reflux disease (GERD) and obesity. Lipid metabolism‐targeted therapies decrease the risk of progressing from Barrett's esophagus (BE) to EAC, but the precise lipid metabolic changes and their roles in genotoxicity during EAC development are yet to be established. Methods Esophageal biopsies from the normal epithelium (NE), BE, and EAC, were analyzed using concurrent lipidomics and proteomics ( n = 30) followed by orthogonal validation on independent samples using RNAseq transcriptomics ( n = 22) and immunohistochemistry (IHC, n = 80). The EAC cell line FLO‐1 was treated with FADS2 selective inhibitor SC26196, and/or bile acid cocktail, followed by immunofluorescence staining for γH2AX. Results Metabolism‐focused Reactome analysis of the proteomics data revealed enrichment of fatty acid metabolism, ketone body metabolism, and biosynthesis of specialized pro‐resolving mediators in EAC pathogenesis. Lipidomics revealed progressive alterations (NE‐BE‐EAC) in glycerophospholipid synthesis with decreasing triglycerides and increasing phosphatidylcholine and phosphatidylethanolamine, and sphingolipid synthesis with decreasing dihydroceramide and increasing ceramides. Furthermore, a progressive increase in lipids with C20 fatty acids and polyunsaturated lipids with ≥4 double bonds were also observed. Integration with transcriptome data identified candidate enzymes for IHC validation: Δ4‐Desaturase, Sphingolipid 1 (DEGS1) which desaturates dihydroceramide to ceramide, and Δ5 and Δ6‐Desaturases (fatty acid desaturases, FADS1 and FADS2), responsible for polyunsaturation. All three enzymes showed significant increases from BE through dysplasia to EAC, but transcript levels of DEGS1 were decreased suggesting post‐translational regulation. Finally, the FADS2 selective inhibitor SC26196 significantly reduced polyunsaturated lipids with three and four double bonds and reduced bile acid‐induced DNA double‐strand breaks in FLO‐1 cells in vitro. Conclusions Integrated multiomics revealed sphingolipid and phospholipid metabolism rewiring during EAC development. FADS2 inhibition and reduction of the high polyunsaturated lipids effectively protected EAC cells from bile acid‐induced DNA damage in vitro, potentially through reduced lipid peroxidation.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 60%

Elevation of fatty acid desaturase 2 in esophageal adenocarcinoma increases polyunsaturated lipids and may exacerbate bile acid‐induced DNA damage

Molendijk

Kolka

Cairns

et al. 2022

Clinical & Translational Med

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“…However, in addition to dysregulated EEC barrier function, other studies suggest that immune-mediated mechanisms are also likely to be important and may even precede loss of epithelial barrier function (429). Furthermore, several studies suggest that bile acids are likely to contribute to this immune-driven response, since exposure of esophageal squamous epithelial cell lines and ex vivo mucosal tissues to bile acids significantly increases expression of cyclooxygenase-2 and inducible nitric oxide synthase, and secretion of the proinflammatory cytokines IL-8 and IL-1␤, leading to enhanced migration of T cells and neutrophils into the mucosa (191,293,417,429). Increased expression of FXR in the epithelium appears to be involved in mediating such responses (54,92,460), and a combination of acidic media with bile acids seems to be important.…”

Section: E Bile Acids and Gerdmentioning

confidence: 99%

Guts and Gall: Bile Acids in Regulation of Intestinal Epithelial Function in Health and Disease

Hegyi

Maléth

Walters

et al. 2018

Physiological Reviews

207

152

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Epithelial cells line the entire surface of the gastrointestinal tract and its accessory organs where they primarily function in transporting digestive enzymes, nutrients, electrolytes, and fluid to and from the luminal contents. At the same time, epithelial cells are responsible for forming a physical and biochemical barrier that prevents the entry into the body of harmful agents, such as bacteria and their toxins. Dysregulation of epithelial transport and barrier function is associated with the pathogenesis of a number of conditions throughout the intestine, such as inflammatory bowel disease, chronic diarrhea, pancreatitis, reflux esophagitis, and cancer. Driven by discovery of specific receptors on intestinal epithelial cells, new insights into mechanisms that control their synthesis and enterohepatic circulation, and a growing appreciation of their roles as bioactive bacterial metabolites, bile acids are currently receiving a great deal of interest as critical regulators of epithelial function in health and disease. This review aims to summarize recent advances in this field and to highlight how bile acids are now emerging as exciting new targets for disease intervention.

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“…These data suggest that exposure of cystic cholangiocytes to TGR5 agonists might account for overexpression of both TGR5 and Gα s in PLD, leading to cAMP elevation. An increased expression of TGR5 upon exposure to its ligands has also been observed in esophageal epithelium, gastric myenteric plexus, and macrophages …”

Section: Discussionmentioning

confidence: 93%

“…An increased expression of TGR5 upon exposure to its ligands has also been observed in esophageal epithelium, gastric myenteric plexus, and macrophages. (35)(36)(37) To our knowledge, no reports describe the identification, synthesis, or pharmacologic activity of TGR5 antagonists. SBI-115 (further details of which will be published elsewhere), a novel small molecule, was identified from a high-throughput screen in CHO-K1 cells expressing TGR5.…”

Section: Discussionmentioning

confidence: 99%

TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling

Masyuk¹,

Masyuk²,

Pisarello³

et al. 2017

Hepatology

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Hepatic cystogenesis in Polycystic Liver Disease (PLD) is associated with increased levels of cAMP in cholangiocytes lining liver cysts. TGR5, a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with PLD. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to: (i) TGR5 agonists [taurolithocholic acid (TLCA), oleanolic acid (OA) and two synthetic compounds]; (ii) a novel TGR5 antagonist (SBI-115); and (iii) a combination of SBI-115 and pasireotide, a somatostatin receptor (SSTR) analog. In vivo, we examined hepatic cystogenesis in OA-treated PCK rats and after genetic elimination of TGR5 in double mutant TGR5−/−;Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq) proteins was increased 2–3-fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation and cyst growth by ~40%; these effects were abolished after TGR5 reduction by shRNA. OA increased cystogenesis in PCK rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5-deficient TGR5−/−;Pkhd1del2/del2 mice. TGR5 expression and its co-localization with Gαs were increased ~2-fold upon OA treatment. Levels of cAMP, cell proliferation and cyst growth in vitro were decreased by ~30% in cystic cholangiocytes after treatment with SBI-115 alone and by ~50% when SBI-115 was combined with pasireotide. Conclusion: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation. Our data suggest that a TGR5 antagonist alone or concurrently with SSTR agonists represents novel therapeutic approaches in PLD.

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Controlled bile acid exposure to oesophageal mucosa causes up-regulation of nuclear γ-H2AX possibly via iNOS induction

Abstract: The results of the present study provide suggestion that not only acid reflux, but also non-acid reflux of bile may cause genotoxic stress. These aspects merit to be tested in wide spectrum of Barrett epithelial tissues.

Cited by 7 publications

References 25 publications

Elevation of fatty acid desaturase 2 in esophageal adenocarcinoma increases polyunsaturated lipids and may exacerbate bile acid‐induced DNA damage

Elevation of fatty acid desaturase 2 in esophageal adenocarcinoma increases polyunsaturated lipids and may exacerbate bile acid‐induced DNA damage

Guts and Gall: Bile Acids in Regulation of Intestinal Epithelial Function in Health and Disease

TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling

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