Upregulation of BAK by butyrate in the colon is associated with increased Sp3 binding

Chirakkal, Haridasan; Leech, Siân H.; Brookes, K E; Prais, Anna L.; Waby, Jennifer S.; Corfe, Bernard M.

doi:10.1038/sj.onc.1209702

Cited by 67 publications

(75 citation statements)

References 33 publications

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“…TSA has also been described to modulate the acetylation of Sp1 and subsequently upregulate transcription of transforming growth factor type II receptor gene (26). GC-rich regions of promoter sequences have previously been shown to be activated by butyrate through Sp1 or Sp3 binding (7,13,42). Interestingly, one such putative Sp1 binding site was found in the butyrate and TSA-responsive element within the 0.5 kb fragment of ANGPTL4 promoter (at position Ϫ362).…”

Section: Discussionmentioning

confidence: 94%

ANGPTL4 expression induced by butyrate and rosiglitazone in human intestinal epithelial cells utilizes independent pathways

Korecka

Wouters

Cultrone

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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-Short-chain fatty acids (SCFAs), such as butyrate and propionate, are metabolic products of carbohydrate fermentation by the microbiota and constitute the main source of energy for host colonocytes. SCFAs are also important for gastrointestinal health, immunity, and host metabolism. Intestinally produced angiopoietin-like protein 4 (ANGPTL4) is a secreted protein with metabolism-altering properties and may offer a route by which microbiota can regulate host metabolism. Peroxisome proliferator-activated receptor (PPAR)-␥ has previously been shown to be involved in microbiota-induced expression of intestinal ANGPTL4, but the role of bacterial metabolites in this process has remained elusive. Here, we show that the SCFA butyrate regulates intestinal ANGPTL4 expression in a PPAR-␥-independent manner. Although PPAR-␥ is not required for butyrate-driven intestinal ANGPTL4 expression, costimulating with PPAR-␥ ligands and SCFAs leads to additive increases in ANGPTL4 levels. We suggest that PPAR-␥ and butyrate rely on two separate regulatory sites, a PPAR-responsive element downstream the transcription start site and a butyrate-responsive element(s) within the promoter region, 0.5 kb upstream of the transcription start site. Furthermore, butyrate gavage and colonization with Clostridium tyrobutyricum, a SCFA producer, can independently induce expression of intestinal ANGPTL4 in germ-free mice. Thus, oral administration of SCFA or use of SCFA-producing bacteria may be additional routes to maintain intestinal ANGPTL4 levels for preventive nutrition or therapeutic purposes.short-chain fatty acids; peroxisome proliferator-activated receptor-␥; fasting-induced adipose factor; angiopoietin-like protein 4; Clostridium tyrobutyricum THE HUMAN GASTROINTESTINAL (GI) tract has long been perceived as an organ with purely digestive functions. This perception has radically changed over the last decades as it emerged that the function of the GI tract is not only limited to energy uptake but also affects regulatory processes with wide-ranging systemic effects. These are either directly related to its digestive functions or independent ones impacting on local and systemic inflammation (reviewed in Ref. This crosstalk contributes among other things to the physiological state of the IEC including maturation and the integrity of the overall epithelial barrier (53). The importance of a well-regulated response to the intestinal microbiota and its metabolites has repeatedly been shown to be crucial to the health of the host (reviewed in Refs. 12 and 31).Mouse studies have also linked intestinal colonization to the capacity of energy utilization and weight gain (5, 6). One mechanism implied in this process is the regulation of angiopoietin-like protein 4 (ANGPTL4) expression in the intestinal epithelium. ANGPTL4 is a secreted protein with a variety of functions ranging from regulation of lipid and glucose homeostasis to inhibition of cell migration and angiogenesis (reviewed in Ref. 21). The NH 2 -terminal domain of ANGPTL4 inhibits lipoprote...

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Section: Discussionmentioning

confidence: 94%

ANGPTL4 expression induced by butyrate and rosiglitazone in human intestinal epithelial cells utilizes independent pathways

Korecka

Wouters

Cultrone

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Expression of Puma for instance can also be induced by FoxO3 and SP1. 26,27 Interestingly, Chirakkal et al 28 identified a SP1-binding site within the bak1 promoter that was also indicated in our MatInspector analysis (Figure 1). This SP1-binding site mediates upregulation of Bak in response to butyrate as well as basal Bak expression.…”

Section: Discussionmentioning

confidence: 96%

Differential regulation of the proapoptotic multidomain protein Bak by p53 and p73 at the promoter level

et al. 2011

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During apoptosis Bcl-2 proteins control permeabilization of the mitochondrial outer membrane leading to the release of cytochrome c. Essential gatekeepers for cytochrome c release are the proapoptotic multidomain proteins, Bax, and Bak. The expression of Bax is upregulated upon cellular stress by the tumor suppressor p53. Despite the high functional homology of Bax and Bak, little is known about how the bak gene is regulated. To investigate its transcriptional regulation in further detail, we have analyzed a region spanning 8200 bp upstream of the bak start codon (within exon 2) for transcription factor-binding sites, and identified three p53 consensus sites (BS1-3). Reporter gene assays in combination with site-directed mutagenesis revealed that only one putative p53-binding site (BS3) is necessary and sufficient for induction of reporter gene expression by p53. Consistently, p53 induces expression of endogenous Bak. At the mRNA level, induction of Bak expression is weaker than induction of Puma and p21. Interestingly, Bak expression can also be induced by p73 that binds however to each of the three p53-binding sites within the bak promoter region. Our data suggest that expression of Bak can be induced by both, p53 and p73 utilizing different binding sites within the bak promoter.

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“…This can reduce the burden of carcinogens, such as BAs, and therefore decrease the number of mutations, which reduces cancer risk. Experimental studies have shown that it regulates colonic epithelial growth and protects against carcinogenesis by inhibiting the proliferation and migration of neoplastic cells, restricting tumor angiogenesis, inducing apoptosis, and promoting differentiation of the neoplastic colonocytes (43)(44)(45)(46)(47)(48)(49). F. prausnitzii, a member of Clostridium cluster IV, is one of the most dominant butyrate producers, but also may have independent antiinflammatory properties related to secreted metabolites, which have been shown to block nuclear factor kB activation and IL-8 production (50).…”

Section: Discussionmentioning

confidence: 99%

Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans

Carbonero²,

Zoetendal

et al. 2013

The American Journal of Clinical Nutrition

585

418

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Background: Epidemiologic studies have suggested that most cases of sporadic colon cancer can be attributed to diet. The recognition that colonic microbiota have a major influence on colonic health suggests that they might mediate colonic carcinogenesis. Objective: To examine the hypothesis that the influence of diet on colon cancer risk is mediated by the microbiota through their metabolites, we measured differences in colonic microbes and their metabolites in African Americans with a high risk and in rural native Africans with a low risk of colon cancer. Design: Fresh fecal samples were collected from 12 healthy African Americans aged 50-65 y and from 12 age-and sex-matched native Africans. Microbiomes were analyzed with 16S ribosomal RNA gene pyrosequencing together with quantitative polymerase chain reaction of the major fermentative, butyrate-producing, and bile acid-deconjugating bacteria. Fecal short-chain fatty acids were measured by gas chromatography and bile acids by liquid chromatography-mass spectrometry. Results: Microbial composition was fundamentally different, with a predominance of Prevotella in native Africans (enterotype 2) and of Bacteroides in African Americans (enterotype 1). Total bacteria and major butyrate-producing groups were significantly more abundant in fecal samples from native Africans. Microbial genes encoding for secondary bile acid production were more abundant in African Americans, whereas those encoding for methanogenesis and hydrogen sulfide production were higher in native Africans. Fecal secondary bile acid concentrations were higher in African Americans, whereas short-chain fatty acids were higher in native Africans. Conclusion: Our results support the hypothesis that colon cancer risk is influenced by the balance between microbial production of health-promoting metabolites such as butyrate and potentially carcinogenic metabolites such as secondary bile acids.Am J Clin Nutr 2013;98:111-20.

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Upregulation of BAK by butyrate in the colon is associated with increased Sp3 binding

Cited by 67 publications

References 33 publications

ANGPTL4 expression induced by butyrate and rosiglitazone in human intestinal epithelial cells utilizes independent pathways

ANGPTL4 expression induced by butyrate and rosiglitazone in human intestinal epithelial cells utilizes independent pathways

Differential regulation of the proapoptotic multidomain protein Bak by p53 and p73 at the promoter level

Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans

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