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PubMed1997

Butyrate activates the WAF1/Cip1 gene promoter through Sp1 sites in a p53-negative human colon cancer cell line.

Butyrate is a well known colonic luminal short chain fatty acid, which arrests cell growth and induces differentiation in various cell types. We examined the effect of butyrate on the expression of WAF1/Cip1, a potent inhibitor of cyclin-dependent kinases, and its relation to growth arrest in a p53-mutated human colon cancer cell line WiDr. Five millimolar butyrate completely inhibited the growth of WiDr and caused G1-phase arrest. WAF1/Cip1 mRNA was rapidly induced within 3 h by treatment with 5.0 mM butyrate, and drastic WAF1/Cip1 protein induction was detected. Using several mutant WAF1/Cip1 promoter fragments, we found that the butyrate-responsive elements are two Sp1 sites at -82 and -69 relative to the transcription start site. We also found that a TATA element at -46 and two overlapping consensus Sp1 sites at -60 and -55 are essential for the basal promoter activity of WAF1/Cip1. These findings suggest that butyrate arrests the growth of WiDr by activating the WAF1/Cip1 promoter through specific Sp1 sites in a p53-independent fashion.

Base Sequence↗
PubMed1998

Butyric acid from the diet: actions at the level of gene expression.

A number of components present in the diet, although nutritionally nonessential, have been discovered to have beneficial effects toward both general health and disease prevention/protection. One such nutrient, butyric acid, can be derived in large quantities from bacterial fementation of dietary fiber in the bowel and is also a component of bovine milk. In gut fermentation, the production of butyric acid defines its delivery point; thus, the synthesis and site of action of butyric acid are in close proximity and have frustrated the investigation of its activities in vivo. Recent research has, however, revealed a number of activities of butyric acid toward isolated cells. In particular, its ability to modify nuclear architecture and induce death by apoptosis in colon cancer cells is arousing great interest. Butyric acid changes the structure of chromatin through its effects on posttranslational modifications, key modifications being acetylation and phosphorylation of the nuclear histones. Butyric acid can also modify the differentiation state of cells, and in the case of cancerous colonic cells overcomes their resistance to normal programmed death. Thus, the activities of this fermentation product of dietary fiber may contribute substantially to the decreased incidence of bowel cancer that has been associated with fiber intake.

Animals↗
PubMed1986

n-Butyrate alters chromatin accessibility to DNA repair enzymes.

Current evidence suggests that the complex nature of mammalian chromatin can result in the concealment of DNA damage from repair enzymes and their co-factors. Recently it has been proposed that the acetylation of histone proteins in chromatin may provide a surveillance system whereby damaged regions of DNA become exposed due to changes in chromatin accessibility. This hypothesis has been tested by: (i) using n-butyrate to induce hyperacetylation in human adenocarcinoma (HT29) cells; (ii) monitoring the enzymatic accessibility of chromatin in permeabilised cells; (iii) measuring u.v. repair-associated nicking of DNA in intact cells and (iv) determining the effects of n-butyrate on cellular sensitivity to DNA damaging agents. The results indicate that the accessibility of chromatin to Micrococcus luteus u.v. endonuclease is enhanced by greater than 2-fold in n-butyrate-treated cells and that there is a corresponding increase in u.v. repair incision rates in intact cells exposed to the drug. Non-toxic levels of n-butyrate induce a block to G1 phase transit and there is a significant growth delay on removal of the drug. Resistance of HT29 cells to u.v.-radiation and adriamycin is enhanced in n-butyrate-treated cells whereas X-ray sensitivity is increased. Although changes in the responses of cells to DNA damaging agents must be considered in relation to the effects of n-butyrate on growth rate and cell-cycle distribution, the results are not inconsistent with the proposal that increased enzymatic-accessibility/repair is biologically favourable for the resistance of cells to u.v.-radiation damage. Overall the results support the suggested operation of a histone acetylation-based chromatin surveillance system in human cells.

Butyrates↗
PubMed1983

Induction of spermidine N1-acetyltransferase by sodium n-butyrate and phytohemagglutinin in bovine lymphocytes.

An increased activity of spermidine N1-acetyltransferase was induced in bovine lymphocytes by stimulation with either sodium n-butyrate or phytohemagglutinin (PHA). The acetylase activity was elevated by 2- to 3-fold 24 h after the addition of butyrate, whereas a similar increase of the enzyme activity was found 48 h after stimulation with PHA. When butyrate and PHA were added to the lymphocyte suspensions simultaneously, the peak of enzyme induction was observed at 24 h after the addition and the increase (9-fold) was found to be more than additive. Since the increases in acetylase activity by both butyrate and PHA were markedly inhibited by actinomycin D or cycloheximide, they appear to have resulted from the synthesis of new protein rather than the release of the enzyme from a cryptic inactive form. The enzyme induced by the two agents was most active with spermidine as a substrate, but spermine was also acetylated to a smaller extent (25% of spermidine). Virtually no acetylation was observed with putrescine. Also, the product formed from spermidine and acetyl CoA was more than 90% N1-acetylspermidine. These results indicate that the acetylases induced by the two agents are similar. Although the addition of indomethacin or 8-bromocyclic AMP to PHA-stimulated lymphocytes caused an inhibition of the enzyme induction, no such inhibitory effect was found in the case of enzyme induction by butyrate. These results indicate that both sodium n-butyrate and PHA induce spermidine N1-acetyltransferase in bovine lymphocytes, but the induction mechanisms are different from each other.

Acetyltransferases↗
PubMed1993

Sodium butyrate inhibits rat insulinoma cell proliferation without affecting the cellular insulin content or insulin release.

The short-chain carboxylic acid sodium butyrate is known to induce differentiation in several cell systems. In this paper we have investigated the effect of sodium butyrate on the growth rate and hormone content and secretion in clonal rat insulinoma cells (RINm5F). Special attention was paid to the role of polyamines for these processes, since these compounds have been implicated in the regulation of growth and function of insulin-producing cells. For this purpose RINm5F cells were maintained in culture for 4 days in the presence or absence of 1-2 mM sodium butyrate. It was found that sodium butyrate dose-dependently inhibited the proliferative activity of the RINm5F cells along with a decreased cellular polyamine content. The cellular content of insulin and secretion of the hormone into the culture medium were, however, not altered by sodium butyrate treatment, and neither did this treatment impose a glucose-sensitive insulin release. The decreased polyamine content was restored by the concomitant addition of exogenous putrescine; however, despite this, the reduced cell proliferation persisted. From these findings we conclude that the decreased growth rate evoked by sodium butyrate results from other events than specific polyamine synthesis inhibition. It is furthermore demonstrated that the processes of cell proliferation and regulation of cellular insulin content and secretion can be dissociated in the RINm5F cell line.

Animals↗
PubMed1987

Ultrastructural differentiation and CEA expression of butyrate-treated human pancreatic carcinoma cells.

The effects of butyrate (a biological response modifier) on cellular morphologic features and carcinoembryonic antigen (CEA) expression of human pancreatic carcinoma cells were studied and compared in a well-differentiated, CEA-producing cell line (CAPAN-1), and a poorly differentiated cell line (PANC-1). Butyrate treatment resulted in the acquisition of phenotypic traits commonly attributed to increased "differentiation," including a twofold increase in doubling time, decreased saturation densities, and approximately 50% reduction in colony forming efficiency in both cell lines. Elongation and flattening of cells with extending cellular processes were seen by light microscopy. Significant ultrastructural changes were seen only in the PANC-1 cells, including an increased number of intercellular desmosomes, tonofilaments, and lipid droplets. In contrast, to the coarsely clumped nuclear chromatin (heterochromatin) of untreated PANC-1 cells, the nuclei of the butyrate-treated cells consisted of finely dispersed chromatin (euchromatin). CAPAN-1 cells responded to butyrate with increased CEA synthesis and release. This effect was greatest in the stationary growth phase. Butyrate had no effect on the already low rate of CEA synthesis by PANC-1 cells. These studies suggest that CEA synthesis and state of differentiation are affected independently by butyrate treatment and that the original tumor phenotype plays an important role in response to such treatment.

Adenocarcinoma↗
PubMed1989

Effect of sodium butyrate, a differentiating agent, on cell surface glycoconjugates of a human pancreatic cell line.

The effects of sodium butyrate, a differentiating agent, on growth properties and glycoconjugates of a human pancreatic carcinoma cell line (CAPAN-1) were studied. Butyrate caused marked changes of in vitro growth properties including prolongation of doubling time and greatly reduced colony forming efficiency in soft agar. Cell surface labeling revealed significant alterations in proteins and glycoproteins after treatment with sodium butyrate (appearance of glycoproteins of molecular weight 250,000, 220,000, and 70,000; reduction of glycoproteins of 164,000, 148,000, 110,000, and 66,800 sizes; increases in proteins/glycoproteins of 85,000 and 78,000). Metabolic labeling of the cells with [3H]fucose or [3H]galactose revealed that sodium butyrate treatment caused a marked reduction in the fucose-containing neutral glycolipids with six or more carbohydrate side chains and an increase in [3H]galactose-labeled neutral glycolipids, particularly GL-3a, GL-4a, and GL-5a. There was marked reduction in the labeling of a ganglioside with mobility similar to that of GM4 and of sulfogalactosylceramide. An increase in a ganglioside with mobility above GM1 was also caused by butyrate. These data indicate that sodium butyrate may be useful in the identification of differentiation or malignancy-associated glycoconjugate markers of human pancreatic cells.

Butyrates↗
PubMed1991

Ultrastructural differentiation of sodium butyrate-treated human pancreatic adenocarcinoma cell lines.

The differentiation effects of sodium butyrate were examined in a series of human pancreatic adenocarcinoma cell lines: Panc-1, a poorly differentiated cell line; HPAF, a pleomorphic cell line isolated in this laboratory; and two clones of the parental HPAF cell line, well-differentiated CD11 and less-differentiated CD18. Incubation with 2 mM sodium butyrate induced a dramatic decrease in cell proliferation and saturation densities in culture and an increase in alkaline phosphatase activity. Of particular interest, incubation with sodium butyrate also caused a number of morphologic alterations in these cells, attributed to an induction of secretory differentiation. Following sodium butyrate treatment, CD18 cells were virtually indistinguishable from the more highly differentiated CD11 cells as evidenced by an increase in the number of profiles of rough endoplasmic reticulum and of Golgi. Intercellular and intracytoplasmic lumens, whose appearance is quite common in CD11 cells but nonexistent in untreated CD18 cells, appeared in these cells following only 5 days of sodium butyrate treatment. An increase in the cytoplasmic secretory elements was also observed in sodium butyrate-treated Panc-1 cells; however, lumen formation never occurred in these cells.

Adenocarcinoma↗
PubMed1985

Effect of sodium butyrate on the complexity and the translation activity of hepatoma tissue-cultured cell RNAs.

We have studied the effect of sodium butyrate on RNA populations and on the in vitro translation pattern of RNA from Hepatoma Tissue-Cultured (HTC) cells. Since sodium butyrate inhibits cell growth we have used stationary cells as control. Molecular hybridization study of cDNA with polyadenylated RNAs shows that sodium butyrate induces the formation of additional 15% new RNA sequences, essentially in the class of abundant sequences and of sequences of intermediary abundance. This drug also decreases 5-10 times the frequency of the sequences of intermediary abundance. One- and two-dimensional polyacrylamide gel electrophoreses of the translational products of RNAs show that sodium butyrate induces or strongly increases the synthesis of 13 polypeptides and decreases the synthesis of 6 polypeptides, which is consistent with the effect of sodium butyrate on RNA populations and could result from the effect of this drug at both transcriptional and early post-transcriptional steps. Electrophoretic analysis of the in vitro translation products of RNAs from cells submitted to sodium butyrate and transferred to a normal medium for various lengths of time shows that most of the polypeptides return to a normal pattern after a certain length of time which varies according to the polypeptide.

Animals↗
PubMed1993

Effects of acetate, propionate, and butyrate on the thermophilic anaerobic degradation of propionate by methanogenic sludge and defined cultures.

The effects of acetate, propionate, and butyrate on the anaerobic thermophilic conversion of propionate by methanogenic sludge and by enriched propionate-oxidizing bacteria in syntrophy with Methanobacterium thermoautotrophicum delta H were studied. The methanogenic sludge was cultivated in an upflow anaerobic sludge bed (UASB) reactor fed with propionate (35 mM) as the sole substrate for a period of 80 days. Propionate degradation was shown to be severely inhibited by the addition of 50 mM acetate to the influent of the UASB reactor. The inhibitory effect remained even when the acetate concentration in the effluent was below the level of detection. Recovery of propionate oxidation occurred only when acetate was omitted from the influent medium. Propionate degradation by the methanogenic sludge in the UASB reactor was not affected by the addition of an equimolar concentration (35 mM) of butyrate to the influent. However, butyrate had a strong inhibitory effect on the growth of the propionate-oxidizing enrichment culture. In that case, the conversion of propionate was almost completely inhibited at a butyrate concentration of 10 mM. However, addition of a butyrate-oxidizing enrichment culture abolished the inhibitory effect, and propionate oxidation was even stimulated. All experiments were conducted at pH 7.0 to 7.7. The thermophilic syntrophic culture showed a sensitivity to acetate and propionate similar to that of mesophilic cultures described in the literature. Additions of butyrate or acetate to the propionate medium had no effect on the hydrogen partial pressure in the biogas of an UASB reactor, nor was the hydrogen partial pressure in propionate-degrading cultures affected by the two acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1993

Effects of hydrogen and formate on the degradation of propionate and butyrate in thermophilic granules from an upflow anaerobic sludge blanket reactor.

Degradation of propionate and butyrate in whole and disintegrated granules from a thermophilic (55 degrees C) upflow anaerobic sludge blanket reactor fed with acetate, propionate, and butyrate as substrates was examined. The propionate and butyrate degradation rates in whole granules were 1.16 and 4.0 mumol/min/g of volatile solids, respectively, and the rates decreased 35 and 25%, respectively, after disintegration of the granules. The effect of adding different hydrogen-oxidizing bacteria (both sulfate reducers and methanogens), some of which used formate in addition to hydrogen, to disintegrated granules was tested. Addition of either Methanobacterium thermoautotrophicum delta H, a hydrogen-utilizing methanogen that does not use formate, or Methanobacterium sp. strain CB12, a hydrogen- and formate-utilizing methanogen, to disintegrated granules increased the degradation rate of both propionate and butyrate. Furthermore, addition of a thermophilic sulfate-reducing bacterium (a Desulfotomaculum sp. isolated in our laboratory) to disintegrated granules improved the degradation of both substrates even more than the addition of methanogens. By monitoring the hydrogen partial pressure in the cultures, a correlation between the hydrogen partial pressure and the degradation rate of propionate and butyrate was observed, showing a decrease in the degradation rate with increased hydrogen partial pressure. No significant differences in the stimulation of the degradation rates were observed when the disintegrated granules were supplied with methanogens that utilized hydrogen only or hydrogen and formate. This indicated that interspecies formate transfer was not important for stimulation of propionate and butyrate degradation.

Anaerobiosis↗
PubMed1984

Independent regulation by sodium butyrate of gonadotropin alpha gene expression and cell cycle progression in HeLa cells.

Sodium butyrate alters the growth and gene expression of a variety of differentiating and neoplastic cell types. For example, addition of 5 mM butyrate to HeLa cells is reported to both induce gonadotropin alpha subunit biosynthesis and block cell cycling in G1. We have studied these two actions of butyrate on HeLa cells and found that they are regulated in distinct ways. The induction of alpha subunit synthesis was due to an increase in the rate of transcription of the alpha gene. Using synchronized populations of HeLa cells, we determined that butyrate stimulates alpha transcription throughout the cell cycle. In contrast, treated cells arrest in G1 only if exposed to butyrate for a discrete period during the previous S phase. We conclude that butyrate inhibits DNA synthesis through a cell cycle-specific action that is independent from its direct action to stimulate transcription of the gonadotropin alpha gene.

Butyrates↗
PubMed1994

Butyrate oxidation is impaired in the colonic mucosa of sufferers of quiescent ulcerative colitis.

The short chain fatty acids, acetate, propionate, and butyrate are produced by colonic bacterial fermentation of non-starch polysaccharides. Butyrate is the major fuel source for the colonic epithelium and there is evidence to suggest that its oxidation is impaired in ulcerative colitis. Triplicate biopsy specimens were taken at colonoscopy from five regions of the large bowel in 15 sufferers of ulcerative colitis. These patients all had mild or quiescent colitis as assessed by clinical condition, mucosal endoscopic and histological appearance. The rate of oxidation of glucose, glutamine, and butyrate through to carbon dioxide was compared with that in biopsy specimens from 28 patients who had no mucosal abnormality. Butyrate (272 (199-368)) was the preferred fuel source for the colitic mucosa followed by glutamine (33 (24-62)) then glucose (7.2 (5.3-15)) pmol/micrograms/hour; medians and 95% confidence intervals, p < 0.01. There was no regional difference in the rate of utilisation of these metabolites. In the group with colitis the rate of butyrate oxidation to carbon dioxide was significantly impaired compared with that in normal mucosa decreasing from 472 (351-637) pmol/micrograms/hour to 272 (199-368) pmol/micrograms/hour; median and 95% confidence intervals, p = 0.016. The rate of glucose and glutamine utilisation were not significantly different between normal and colitic mucosa. These data confirm that in quiescent ulcerative colitis there is an impairment of butyrate oxidation.

Adult↗
PubMed1995

Colonic mucin synthesis is increased by sodium butyrate.

The effects of sodium butyrate and sodium bromo-octanoate (an inhibitor of beta oxidation) on colonic mucus glycoprotein (mucin) synthesis have been assessed using tissue from colonic resection samples. Epithelial biopsy specimens were incubated for 16 hours in RPMI 1640 with glutamine, supplemented with 10% fetal calf serum and N-acetyl-[3H]-glucosamine ([3H]-Glc NAc), and differing concentrations of sodium butyrate. Incorporation of [3H] Glc NAc into mucin by normal epithelium at least 10 cm distant from colonic cancer was increased in the presence of sodium butyrate in a dose dependent manner, with maximum effect (476%) at a concentration of 0.1 mM (number of specimens = 24 from six patients, p < 0.001). The increase in response to butyrate was not seen when specimens were incubated in the presence of the beta oxidation inhibitor sodium bromo-octanoate 0.05 M. The striking increase in mucin synthesis that results when butyrate is added to standard nutrient medium suggests that this may be an important mechanism affecting the rate of mucin synthesis in vivo and may also explain the therapeutic effect of butyrate in colitis.

Adult↗
PubMed1998

Fetal lung mRNA levels of Hox genes are differentially altered by maternal diabetes and butyrate in rats.

Diabetes is known to be associated with delayed lung development in humans and in experimental animals. This includes delayed expression of surfactant apoproteins. An important component of the metabolic abnormalities in diabetes is elevated levels of analogs of butyric acid, and the effects of diabetes on surfactant apoproteins can be reproduced by exposure of fetal rat lung explants to butyrate. Dexamethasone has the opposite effects on lung development. In humans, antenatal exposure to dexamethasone results in a lower incidence of RDS, whereas in experimental animals, dexamethasone increases the expression of surfactant apoproteins. A subset of Hox genes are expressed in developing lung, and their level of expression decreases with advancing gestation. We hypothesized that: 1) lungs of fetuses of rats with streptozotocin-induced diabetes would have altered levels of expression of Hox genes, 2) the effect would be mediated in part through elevated levels of butyrate, and 3) dexamethasone would reverse the effect. We tested our hypotheses in vivo using fetuses from streptozotocin-treated rats and in vitro by treating lung explants from normal rats with sodium butyrate. Streptozotocin treatment increased expression of Hoxb-5 at 18 d of gestation, but did not affect Hoxa-5 expression. This was associated with a 20-fold increase in alpha-aminobutyrate levels. Dexamethasone tended to reverse this effect. In contrast, butyrate treatment of explants decreased the expression of Hoxa-5 and Hoxb-5. We conclude that diabetes alters expression of Hox genes, but that the effect of butyrate on lung development, and in particular on surfactant apoprotein expression, is independent of its effects on Hox genes.

Animals↗
PubMed1989

Sodium butyrate enhances fetal globin gene expression in erythroid progenitors of patients with Hb SS and beta thalassemia.

Increasing the expression of the gamma globin genes is considered a useful therapeutic approach to the beta globin diseases. Because butyrate and alpha-amino-n-butyric acid (ABA) augment gamma globin expression in normal neonatal and adult erythroid progenitors, we investigated the effects of sodium butyrate and ABA on erythroid progenitors of patients with beta thalassemia and sickle cell anemia who might benefit from such an effect. Both substances increased fetal hemoglobin (Hb F) expression in Bfu-e from 7% to 30% above levels found in control cultures from the same subjects with sickle cell anemia. The fraction of cultured erythroblasts producing Hb F increased more than 20% with sodium butyrate treatment in 70% of cultures. In most cultures, this produced greater than 20% total Hb F and greater than 70% F cells, levels which have been considered beneficial in ameliorating clinical symptoms. Alpha: non-alpha (alpha-non-alpha) imbalance was decreased by 36% in erythroid progenitors of patients with beta thalassemia cultured in the presence of butyrate compared with control cultures from the same subjects. These data suggest that sodium butyrate may have therapeutic potential for increasing gamma globin expression in the beta globin diseases.

Anemia, Sickle Cell↗
PubMed1989

Alterations in the expression of pp60c-src and p56lck associated with butyrate-induced differentiation of human colon carcinoma cells.

The effects of butyrate-mediated differentiation of human colon carcinoma cells on the expression of src-related tyrosine protein kinases were analyzed. The results demonstrate that treatment of a variety of colon carcinoma cell lines with 2 mM sodium butyrate resulted in diminished population doubling rates, altered morphology, decreased anchorage-independent growth, and increased expression of colon epithelial differentiation marker enzymes such as alkaline phosphatase. In butyrate-treated cells, significantly diminished protein kinase activities and abundance of pp60c-src and p56lck were found to parallel the butyrate-induced phenotypic alterations. For the lck gene, the decreased levels in p56lck abundance were found to coincide with diminished levels of steady-state lck mRNAs. In contrast, treatments which arrested the growth of the colon carcinoma cells without inducing differentiation had no effect on the level of expression of these proteins. Furthermore, colon carcinoma cell lines which were found to be resistant to butyrate-induced differentiation showed no change in the kinase activity or abundance of either protein following butyrate treatment. These results indicate that the expression of several src-related kinases in human colon carcinoma can be influenced by the differentiation state of the cells.

Alkaline Phosphatase↗
PubMedDate not supplied

Regulation of hepatocyte epidermal growth factor receptors by n-butyrate and dimethyl sulfoxide: sensitivity to modulation by the tumor promoter TPA.

n-Butyrate and dimethyl sulfoxide (DMSO) are known to promote differentiated characteristics in certain cells, including hepatocytes. We have previously reported that butyrate up-regulates the surface expression of hepatocyte epidermal growth factor (EGF) receptors and preserves a high-affinity receptor subpopulation. In the present study, culturing of hepatocytes with DMSO dose-dependently (0.5-2%) increased EGF binding and maintained a high-affinity binding component which was otherwise down-regulated during culturing. Although butyrate was more effective than DMSO in most experiments, the two agents caused qualitatively the same alteration in hepatocyte EGF receptor status. The high-affinity component of the EGF binding present in cells treated with butyrate or DMSO was reduced by treatment (10 nM-1 microM, 1 h) with the phorbol ester tumor promoter TPA, an activator of protein kinase C. Butyrate- or DMSO-treated hepatocytes were more susceptible to this response to TPA than were untreated hepatocytes. The present data indicate that in hepatocytes both butyrate and DMSO preserve a high-affinity EGF receptor subpopulation which is otherwise down-regulated during hepatocyte culture, and that this effect particularly comprises receptors that are sensitive to modulation by the tumor promoter TPA.

Animals↗