Bile acid toxicity structure–activity relationships: Correlations between cell viability and lipophilicity in a panel of new and known bile acids using an oesophageal cell line (HET-1A)

Sharma, Ruchika; Majer, Ferenc; Peta, Vijaya Kumar; Wang, Jun; Keaveney, Ray; Kelleher, Dermot; Long, Aideen; Gilmer, John F.

doi:10.1016/j.bmc.2010.07.030

Cited by 53 publications

(41 citation statements)

References 51 publications

(74 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The question as to why the specific subset of bile acids (DCA, CDCA, LCA) perturbs the protein secretory pathway may relate to bile acid physiochemical properties and propensity to induce cell death in the HET-1A cell line. In a previous study we showed that DCA, CDCA and LCA significantly decreased HET-1A cell viability at 500 μM concentration [18]. In this study we show that, using sub-lethal concentrations of the panel of bile acids tested (300 μM), only DCA, CDCA and LCA activated eIF-2α in oesophageal cells and that only these bile acids caused Golgi fragmentation.…”

Section: Discussionsupporting

confidence: 63%

“…The panel consisted of DCA, CDCA, UDCA, CA, their glycine and taurine conjugates and LCA. Bile acids were screened at 300 μM (except LCA) as we previously demonstrated that this concentration does not lead to apoptosis in the 6 h time frame used during the experiment and LCA was tested at 25 μM, as we previously demonstrated that higher concentrations were cytotoxic [18]. These concentrations fall within the concentration range of bile acids found in the oesophagus in patients with the precancerous condition Barrett's metaplasia [19].…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Unconjugated secondary bile acids activate the unfolded protein response and induce golgi fragmentation via a src-kinase-dependant mechanism

et al. 2016

Self Cite

View full text Add to dashboard Cite

Bile acids are components of gastro-duodenal refluxate and regarded as causative agents in oesophageal disease but the precise mechanisms are unknown. Here we demonstrate that a specific subset of physiological bile acids affect the protein secretory pathway by inducing ER stress, activating the Unfolded Protein Response (UPR) and causing disassembly of the Golgi apparatus in oesophageal cells. Deoxycholic acid (DCA), Chemodeoxycholic acid (CDCA) and Lithocholic acid (LCA) activated the PERK arm of the UPR, via phosphorylation of eIF2α and up-regulation of ATF3, CHOP and BiP/GRP78. UPR activation by these bile acids is mechanistically linked with Golgi fragmentation, as modulating the UPR using a PERK inhibitor (GSK2606414) or salubrinal attenuated bile acid-induced effects on Golgi structure. Furthermore we demonstrate that DCA, CDCA and LA activate Src kinase and that inhibition of this kinase attenuated both bile acid-induced BiP/GRP78 expression and Golgi fragmentation. This study highlights a novel mechanism whereby environmental factors (bile acids) impact important cellular processes regulating cell homeostasis, including the UPR and Golgi structure, which may contribute to cancer progression in the oesophagus.

show abstract

Section: Discussionsupporting

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Unconjugated secondary bile acids activate the unfolded protein response and induce golgi fragmentation via a src-kinase-dependant mechanism

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Other studies showed CDCA activated FXR with an EC 50 in the 10 -50 M range, depending on the species (29). DCA at concentrations higher than 100 M could induce apoptosis of colon cancer cells (30), and LCA is more toxic than DCA (31). Thus, 20 M of LCA and 50 M of other bile acids were used to compare their effectiveness in inducing miR-22.…”

Section: Resultsmentioning

confidence: 99%

MiR-22-silenced Cyclin A Expression in Colon and Liver Cancer Cells Is Regulated by Bile Acid Receptor

Yang

Ying

Liu

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: miR-22 has a tumor-suppressive effect, but its regulation remains to be characterized. Results: miR-22 is regulated by bile acid-activated FXR, and CCNA2 is a miR-22 target. Conclusion: FXR-induced miR-22 in inhibiting CCNA2 is a novel pathway for FXR to exert its protective effect in the gastrointestinal tract. Significance: The FXR-miR-22-CCNA2 axis is a novel mechanism for FXR-mediated anti-proliferative effect.

show abstract

“…Structure-activity analysis of BAs showed that the cytotoxicity of naturally occurring BAs can be ranked according to DCA≥LCA≥CDCA>>CA based on assessment in an oesophageal (HET-1A) and hepatic carcinoma (Huh7) cell line, and overall this rank order correlates with lipophilicity. However, the respective taurine and glycine conjugates had no cytotoxic effect on HET-1A cells, which lack BA transporters [52]. Conjugated BAs are fully ionized at physiological pH and are therefore considered membrane impermeable without active transport.…”

Section: Ba In Health and Diseasementioning

confidence: 98%

Bile acids in drug induced liver injury: Key players and surrogate markers

Schadt

Wolf

Philippe

et al. 2016

Clinics and Research in Hepatology and Gastroenterology

View full text Add to dashboard Cite

Bile acid research has gained great momentum since the role of bile acids as key signaling molecules in the enterohepatic circulation was discovered. Their physiological function in regulating their own homeostasis, as well as energy and lipid metabolism make them interesting targets for the pharmaceutical industry in the context of diseases such as bile acid induced diarrhea, bile acid induced cholestasis or nonalcoholic steatohepatitis. Changes in bile acid homeostasis are also linked to various types of drug-induced liver injury (DILI). However, the key question whether bile acids are surrogate markers for monitoring DILI or key pathogenic players in the onset and progression of DILI is under intense investigation. The purpose of this review is to summarize the different facets of bile acids in the context of normal physiology, hereditary defects of bile acid transport and DILI.

show abstract

Bile acid toxicity structure–activity relationships: Correlations between cell viability and lipophilicity in a panel of new and known bile acids using an oesophageal cell line (HET-1A)

Cited by 53 publications

References 51 publications

Unconjugated secondary bile acids activate the unfolded protein response and induce golgi fragmentation via a src-kinase-dependant mechanism

Unconjugated secondary bile acids activate the unfolded protein response and induce golgi fragmentation via a src-kinase-dependant mechanism

MiR-22-silenced Cyclin A Expression in Colon and Liver Cancer Cells Is Regulated by Bile Acid Receptor

Bile acids in drug induced liver injury: Key players and surrogate markers

Contact Info

Product

Resources

About