Enhancement of Endothelial Nitric Oxide Production by Chenodeoxycholic Acids in Patients with Hepatobiliary Diseases.

Chisaki, Keigo; Nakajima, Toshiaki; Iwasawa, Kuniaki; Iida, Hidehiro; Matsumoto, Akira; Tada, Minoru; Komatsu, Yutaka; Hirose, Ken; Miyamoto, Ken‐ichi; Okuda, Yukichi; Shiratori, Yasushi; Goto, Atsuo; Hirata, Yasunobu; Nagai, Ryozo; Omata, Masao

doi:10.1536/jhj.42.339

Cited by 11 publications

(5 citation statements)

References 44 publications

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“…These results are consistent with studies evaluating NO‐mediated bile acid damage and chronic inflammation within the gastrointestinal tract, including one recent report that iNOS knock‐out mice were resistant to deoxycholate‐induced colitis 54. Although esophageal tissues and cell lines had not been evaluated specifically, previous studies have reported increased NO production following exposure to bile acids 55, 56, possibly through increased intracellular Ca 2+ concentrations 57, 58.…”

Section: Discussionsupporting

confidence: 88%

Regulation of CDX2 expression in esophageal adenocarcinoma

Vaninetti

Williams

Geldenhuys

et al. 2009

Molecular Carcinogenesis

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Reflux of acidic gastric contents and bile acids into the lower esophagus has been identified to have a central role in esophageal malignancy and is reported to upregulate caudal-related homologue 2 (CDX2), a regulatory gene involved in embryonic development and axial patterning of the alimentary tract. The aim of this study was to characterize the expression of CDX2 in a well-defined series of human esophageal tissues, comprising reflux-induced esophagitis, premalignant Barrett esophagus (BE), and primary esophageal adenocarcinoma (EADC). To explore potential molecular regulatory mechanisms, we also studied the expression of beta-catenin, SOX9, and CDX2 promoter methylation in esophageal tissues, in addition to the effect of bile acids and nitric oxide (NO) on CDX2 expression in the normal human esophageal cell line Het1A. Relative to matched normal esophageal epithelia, CDX2 was overexpressed in esophagitis (37% for RNA; cytoplasmic immunoreactivity in 48% of tissues), a high proportion (91%) of BE tissues, and in EADC (57% for RNA; cell nuclear immunopositivity in 80%). An association with beta-catenin expression was seen, but not with SOX9 or CDX2 promoter methylation. In Het1A cells, CDX2 was upregulated following exposure to bile acids and NO, alone and in combination. These results further implicate CDX2 and beta-catenin in the molecular pathogenesis of human EADC. The observed synergistic effect of NO on the efficacy of bile acid-induction of CDX2 suggests a novel role for NO in modulating the development of the Barrett phenotype and esophageal adenocarcinogenesis.

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Section: Discussionsupporting

confidence: 88%

Regulation of CDX2 expression in esophageal adenocarcinoma

Vaninetti

Williams

Geldenhuys

et al. 2009

Molecular Carcinogenesis

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“…(21) The most hydrophobic bile acid LCA was not detected in the sera of either healthy subjects or liver cirrhosis patients. (8) The serum concentrations of total bile acid, CDCA, UDCA and CA were markedly higher in patients with hepatobiliary diseases than in healthy subjects. Among these bile acids, CDCA, both free acid and its conjugates, was particularly increased.…”

Section: Discussionmentioning

confidence: 92%

“…Among these bile acids, CDCA, both free acid and its conjugates, was particularly increased. (8) Serum DCA concentrations were shown to be markedly lower than those of the above bile acids in both healthy subjects and patients. (8) GCDCA and TUDCA had relatively lower hydrophobicity with R MW values of 2.92 and 1.71, respectively.…”

Section: Discussionmentioning

confidence: 95%

“…(8) Serum DCA concentrations were shown to be markedly lower than those of the above bile acids in both healthy subjects and patients. (8) GCDCA and TUDCA had relatively lower hydrophobicity with R MW values of 2.92 and 1.71, respectively. (13) GCDCA triggered ER stress and cell death only at concentrations up to 1 mM.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma concentrations of bile acids are commonly elevated in patients with hepatobiliary diseases, (7,8) and high concentrations of bile acids have been shown to result in hepatic inflammatory conditions such as that during cholestasis (9) and eventually cirrhosis. (10) Although the mechanism by which bile acids induce hepatic inflammation is not fully understood, relative hydrophobicity has been suggested to be an important determinant of the biological properties of these compounds.…”

Section: Introductionmentioning

confidence: 99%

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The involvement of endoplasmic reticulum stress in bile acid-induced hepatocellular injury

Adachi

Kaminaga

Yasuda

et al. 2014

J. Clin. Biochem. Nutr.

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Secondary bile acids produced by enteric bacteria accumulate to high levels in the enterohepatic circulation and may contribute to the pathogenesis of hepatocellular injury. Relative hydrophobicity has been suggested to be an important determinant of the biological properties of these compounds, although the mechanism by which bile acids induce pathogenesis is not fully understood. On the other hand, endoplasmic reticulum stress has been shown to be involved in the induction and development of various pathogenic conditions. In this report, we demonstrated that the intensities of cytotoxicity and endoplasmic reticulum stress in HepG2 cells triggered by the bile acids tested were largely dependent on their hydrophobicity. The activation of caspase-3 and DNA fragmentation by treatment with chenodeoxycholic acid showed the contribution of apoptosis to cytotoxicity. Increases in intracellular calcium levels and the generation of reactive oxygen species stimulated by treatment with chenodeoxycholic acid contributed to endoplasmic reticulum stress. Bile acids also induced transforming growth factor-β, a potent profibrogenic factor, which is known to induce hepatocyte apoptosis and ultimately liver fibrosis. In conclusion, our study demonstrated that bile acids induced endoplasmic reticulum stress, which in turn stimulated apoptosis in HepG2 cells, in a hydrophobicity-dependent manner.

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