Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells

Barrasa, Juan I.; Olmo, Nieves; Pérez-Ramos, Pablo; Santiago-Gómez, Angélica; Lecona, Emilio; Turnay, Javier; Lizarbe, M.A.

doi:10.1007/s10495-011-0633-x

Cited by 107 publications

(80 citation statements)

References 44 publications

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“…4), evidencing that apoptosis is a major cell death pathway induced by DCA. In fact, DCA also increased caspase-8-and -9-like activities, up until 52 h of incubation (P Ͻ 0.05) (data not shown), implying the engagement of both the death receptor and the mitochondrial pathways of apoptosis (39). End-stage apoptosis, evaluated using Hoechst staining, confirmed DCA-induced nuclear fragmentation in ϳ30% of cultured hepatocytes throughout the time course (P Ͻ 0.01) (Fig.…”

Section: Resultsmentioning

confidence: 75%

c-Jun N-Terminal Kinase 1/c-Jun Activation of the p53/MicroRNA 34a/Sirtuin 1 Pathway Contributes to Apoptosis Induced by Deoxycholic Acid in Rat Liver

Ferreira

Afonso

Rodrigues

et al. 2014

Molecular and Cellular Biology

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MicroRNAs (miRs) are increasingly associated with metabolic liver diseases. We have shown that ursodeoxycholic acid, a hydrophilic bile acid, counteracts the miR-34a/sirtuin 1 (SIRT1)/p53 pathway, activated in the liver of nonalcoholic steatohepatitis (NASH) patients. In contrast, hydrophobic bile acids, particularly deoxycholic acid (DCA), activate apoptosis and are increased in NASH. We evaluated whether DCA-induced apoptosis of rat hepatocytes occurs via miR-34a-dependent pathways and whether they connect with c-Jun N-terminal kinase (JNK) induction. DCA enhanced miR-34a/SIRT1/p53 proapoptotic signaling in a dose-and time-dependent manner. In turn, miR-34a inhibition and SIRT1 overexpression significantly rescued targeting of the miR-34a pathway and apoptosis by DCA. In addition, p53 overexpression activated the miR-34a/SIRT1/p53 pathway, further induced by DCA. DCA increased p53 expression as well as p53 transcriptional activation of PUMA and miR-34a itself, providing a functional mechanism for miR-34a activation. JNK1 and c-Jun were shown to be major targets of DCA, upstream of p53, in engaging the miR-34a pathway and apoptosis. Finally, activation of this JNK1/miR-34a proapoptotic circuit was also shown to occur in vivo in the rat liver. These results suggest that the JNK1/p53/miR-34a/SIRT1 pathway may represent an attractive pharmacological target for the development of new drugs to arrest metabolism-and apoptosis-related liver pathologies.

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Section: Resultsmentioning

confidence: 75%

c-Jun N-Terminal Kinase 1/c-Jun Activation of the p53/MicroRNA 34a/Sirtuin 1 Pathway Contributes to Apoptosis Induced by Deoxycholic Acid in Rat Liver

Ferreira

Afonso

Rodrigues

et al. 2014

Molecular and Cellular Biology

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“…Primary bile acids have been demonstrated to protect against obesity and insulin resistance (33,36), whereas secondary bile acids are considered potentially toxic and associated with the development of certain cancers (4,21,37). However, it remains unclear whether the balance of primary vs. secondary bile acids is responsible for gastric bypass-mediated metabolic benefits.…”

Section: Bd Results In Improved Adiposity and Glucose Tolerancementioning

confidence: 99%

Activation of bile acid signaling improves metabolic phenotypes in high-fat diet-induced obese mice

Pierre

Martinez

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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EB, Yin DP. Activation of bile acid signaling improves metabolic phenotypes in high-fat diet-induced obese mice. Am J Physiol Gastrointest Liver Physiol 311: G286 -G304, 2016. First published June 23, 2016 doi:10.1152/ajpgi.00202.2016.-The metabolic benefits induced by gastric bypass, currently the most effective treatment for morbid obesity, are associated with bile acid (BA) delivery to the distal intestine. However, mechanistic insights into BA signaling in the mediation of metabolic benefits remain an area of study. The bile diversion () mouse model, in which the gallbladder is anastomosed to the distal jejunum, was used to test the specific role of BA in the regulation of glucose and lipid homeostasis. Metabolic phenotype, including body weight and composition, glucose tolerance, energy expenditure, thermogenesis genes, total BA and BA composition in the circulation and portal vein, and gut microbiota were examined. BD improves the metabolic phenotype, which is in accord with increased circulating primary BAs and regulation of enterohormones. BD-induced hypertrophy of the proximal intestine in the absence of BA was reversed by BA oral gavage, but without influencing BD metabolic benefits. BD-enhanced energy expenditure was associated with elevated TGR5, D2, and thermogenic genes, including UCP1, PRDM16, PGC-1␣, PGC-1␤, and PDGFR␣ in epididymal white adipose tissue (WAT) and inguinal WAT, but not in brown adipose tissue. BD resulted in an altered gut microbiota profile (i.e., Firmicutes bacteria were decreased, Bacteroidetes were increased, and Akkermansia was positively correlated with higher levels of circulating primary BAs). Our study demonstrates that enhancement of BA signaling regulates glucose and lipid homeostasis, promotes thermogenesis, and modulates the gut microbiota, which collectively resulted in an improved metabolic phenotype. bile acids; bile diversion; obesity; energy expenditure; gut microbiota; gastric bypass; mice

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“…While most bile acids aid solubilization of lipids and facilitate nutrient absorption, some are transformed by intestinal bacteria into toxic secondary bile acids in the colon [40]. Thus, the transformation of secondary bile acids in the colon could have cytotoxic effects that may contribute to various gastrointestinal diseases including colorectal cancer [41]–[43]. Therefore, it is possible that Fusobacterium is a commensal that gains from the disruption of intestinal homeostasis as a result of the presence of adenoma or cancer.…”

Section: Discussionmentioning

confidence: 99%

Fusobacterium Is Associated with Colorectal Adenomas

Araújo-Pérez²,

et al. 2013

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The human gut microbiota is increasingly recognized as a player in colorectal cancer (CRC). While particular imbalances in the gut microbiota have been linked to colorectal adenomas and cancer, no specific bacterium has been identified as a risk factor. Recent studies have reported a high abundance of Fusobacterium in CRC subjects compared to normal subjects, but this observation has not been reported for adenomas, CRC precursors. We assessed the abundance of Fusobacterium species in the normal rectal mucosa of subjects with (n = 48) and without adenomas (n = 67). We also confirmed previous reports on Fusobacterium and CRC in 10 CRC tumor tissues and 9 matching normal tissues by pyrosequencing. We extracted DNA from rectal mucosal biopsies and measured bacterial levels by quantitative PCR of the 16S ribosomal RNA gene. Local cytokine gene expression was also determined in mucosal biopsies from adenoma cases and controls by quantitative PCR. The mean log abundance of Fusobacterium or cytokine gene expression between cases and controls was compared by t-test. Logistic regression was used to compare tertiles of Fusobacterium abundance. Adenoma subjects had a significantly higher abundance of Fusobacterium species compared to controls (p = 0.01). Compared to the lowest tertile, subjects with high abundance of Fusobacterium were significantly more likely to have adenomas (OR 3.66, 95% CI 1.37–9.74, p-trend 0.005). Cases but not controls had a significant positive correlation between local cytokine gene expression and Fusobacterium abundance. Among cases, the correlation for local TNF-α and Fusobacterium was r = 0.33, p = 0.06 while it was 0.44, p = 0.01 for Fusobacterium and IL-10. These results support a link between the abundance of Fusobacterium in colonic mucosa and adenomas and suggest a possible role for mucosal inflammation in this process.

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Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells

Cited by 107 publications

References 44 publications

c-Jun N-Terminal Kinase 1/c-Jun Activation of the p53/MicroRNA 34a/Sirtuin 1 Pathway Contributes to Apoptosis Induced by Deoxycholic Acid in Rat Liver

c-Jun N-Terminal Kinase 1/c-Jun Activation of the p53/MicroRNA 34a/Sirtuin 1 Pathway Contributes to Apoptosis Induced by Deoxycholic Acid in Rat Liver

Activation of bile acid signaling improves metabolic phenotypes in high-fat diet-induced obese mice

Fusobacterium Is Associated with Colorectal Adenomas

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