Deoxycholate-Induced Colitis is Markedly Attenuated in Nos2 Knockout Mice in Association with Modulation of Gene Expression Profiles

Bernstein, Harris; Holubec, Hana; Bernstein, Carol; Ignatenko, Natalia A.; Gerner, Eugene W.; Dvorak, Katerina; Besselsen, David G.; Blohm-Mangone, Karen; Padilla-Torres, Jose L.; Dvorakova, Barbora; Garewal, Harinder S.; Payne, Claire M.

doi:10.1007/s10620-006-9608-0

Cited by 22 publications

(20 citation statements)

References 64 publications

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“…We suspect that the atherogenic diets have altered gut microflora composition in these mice. Although high cholesterol diets also increased DCA excretion, since the extent of colitis does not correlate with the DCA levels, this result does not support the role of DCA in colitis as implicated by others (31, 53). …”

Section: Discussioncontrasting

confidence: 68%

Atherogenic diets exacerbate colitis in mice deficient in glutathione peroxidase

Gao

Esworthy

Kim

et al. 2010

Inflammatory Bowel Diseases

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The pro-inflammatory effect of high-fat diet has been observed beyond the cardiovascular system, but there is little evidence to support its role in triggering inflammatory bowel disease. GPx1/2-double knockout (DKO) mice deficient in two intracellular glutathione peroxidases, GPx1 and GPx2, on a C57BL/6 (B6) background, have mild ileocolitis on a conventional chow. We fed B6 DKO mice two atherogenic diets to test the dietary effect on atherosclerosis and ileocolitis. Both atherogenic diets have high cholesterol, the Chol+/CA diet has cholic acid (CA) and the Chol+ diet has no CA. The Chol+/CA diet induced severe colitis, but not ileitis, in the DKO mice compared with Chol+ and a Chol-control diet. On the Chol+/CA diet, the wild-type (WT) mice had similar levels of aortic lesions and hypercholesterolemia as DKO mice did, but had no intestinal pathology. The diet-associated inflammatory responses in the DKO mice included increase of colonic pro-inflammatory serum amyloid A 3 expression, plasma lipopolysaccharide and TNF-α levels. The Chol+/CA diet has lowered the expression of unfolded protein response genes, ATF6, CHOP, unspliced Xbp U and Grp78/Bip, in WT and DKO mice on the Chol-diet. Thus, we conclude that cholesterol diet weakens colon unfolded protein response, which can aggravate spontaneous colitis leading to gut barrier breakdown. GPx has no impact on atherosclerosis without ultra-hypercholesterolemia.

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Section: Discussioncontrasting

confidence: 68%

Atherogenic diets exacerbate colitis in mice deficient in glutathione peroxidase

Gao

Esworthy

Kim

et al. 2010

Inflammatory Bowel Diseases

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“…Some of these post-translationally modified proteins were identified by mass fingerprinting analysis and found to include cytoskeletal proteins, metabolic enzymes, signaling proteins, chaperones, redox-related proteins and differentiation-related proteins 114. We also found that feeding mice deoxycholate can induce inflammation in a mouse model,115 and that the inflammation is mediated in large part by RNS, since colitis is markedly attenuated in NOS2 knockout mice 116…”

Section: Bile Acids Cause Oxidative and Nitrosative Stress In Colon Cmentioning

confidence: 75%

Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis

Payne¹

2008

CEG

122

103

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Sporadic colon cancer is caused predominantly by dietary factors. We have selected bile acids as a focus of this review since high levels of hydrophobic bile acids accompany a Western-style diet, and play a key role in colon carcinogenesis. We describe how bile acid-induced stresses cause cell death in susceptible cells, contribute to genomic instability in surviving cells, impose Darwinian selection on survivors and enhance initiation and progression to colon cancer. The most likely major mechanisms by which hydrophobic bile acids induce stresses on cells (DNA damage, endoplasmic reticulum stress, mitochondrial damage) are described. Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis. The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy. Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described. This review provides a mechanistic explanation for the important link between a Western-style diet and associated increased levels of colon cancer.

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“…There is support for the notion that high concentrations of bile acids in the large intestine may promote colonic abnormalities associated with inflammation. In particular, secondary bile acids such as DOC are pro-inflammatory, as demonstrated in a recent study [3], where supplementing the diet of mice with DOC resulted in colitis. It is thought [4] that DOC is a carcinogen, based on the association of high concentrations of bile acids with several gastrointestinal forms of cancer.…”

Section: Introductionmentioning

confidence: 88%

Protection of human colon epithelial cells against deoxycholate by rottlerin

Longpre

Loo

2008

Apoptosis

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The bile salt, deoxycholate (DOC), can harm cells and cause disease. Hence, there is interest in identifying compounds capable of protecting cells against DOC. In HCT-116 colon epithelial cells, DOC increased generation of reactive oxygen species and caused DNA damage and apoptosis. These effects of DOC were inhibited by rottlerin, which is a phenolic compound of plant origin. In elucidating its mechansim, rottlerin prevented the release of cytochrome c from mitochondria into cytosol, and also prevented the cleavage of caspase-3. Yet, rottlerin by itself markedly decreased mitochondrial membrane potential and increased mitochondrial superoxide production, but this did not result in cytochrome c release or in caspase-3 cleavage. At a higher test concentration, two other phenolic phytochemicals, namely, quercetin and resveratrol, were each able to largely prevent the occurrence of apoptosis in cells exposed to DOC. In contrast, epigallocatechin gallate, curcumin, and genistein were ineffective.

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Deoxycholate-Induced Colitis is Markedly Attenuated in Nos2 Knockout Mice in Association with Modulation of Gene Expression Profiles

Cited by 22 publications

References 64 publications

Atherogenic diets exacerbate colitis in mice deficient in glutathione peroxidase

Atherogenic diets exacerbate colitis in mice deficient in glutathione peroxidase

Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis

Protection of human colon epithelial cells against deoxycholate by rottlerin

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