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PubMed1996

Differential expression and butyrate response of human alkaline phosphatase genes are mediated by upstream DNA elements.

Human placentas express high levels of the placental alkaline phosphatase (PLAP) gene and low levels of a highly related gene, germ cell AP (GCAP). Malignant transformation of the placenta is accompanied by a reversal of this pattern of expression. Three Sp1-binding GC-rich DNA elements (sites I-III) located within the first 156 base pairs upstream of the GCAP gene have been shown to direct optimal GCAP gene expression in choriocarcinoma cells. Here we show that the first 100 base pairs upstream of the GCAP gene, which contains sites I and II, constitutes a minimal GCAP promoter. The simultaneous presence of both sites I and II is necessary for GCAP expression and its induction by sodium butyrate. The PLAP promoter directs only a very low level of gene expression in choriocarcinoma cells; the expression does not respond to butyrate. The -100/-1 DNA regions between the GCAP and PLAP promoters differ by only eight base pairs. However, the GC-rich stretches in sites I and II of the GCAP promoter are disrupted in the corresponding PLAP promoter. This disruption blocks or markedly reduces the binding of choriocarcinoma nuclear factors to the PLAP promoter, leading to a reduction in expression and a loss of butyrate response. We further demonstrate that nucleotides -75 to -58 in both AP promoters, which bind a human Y-box binding protein, appear to down-regulate GCAP expression.

Alkaline Phosphatase↗
PubMed1990

Partial inhibition by cyclosporin A of the swelling of liver mitochondria in vivo and in vitro induced by sub-micromolar [Ca2+], but not by butyrate. Evidence for two distinct swelling mechanisms.

1. The effects of cyclosporin A on the increase in matrix PPi and consequent swelling of energized liver mitochondria incubated with 1 mM-butyrate, 30 microM-bongkrekic acid or 0.1-35 microM-Ca2+ [Halestrap (1989) Biochim. Biophys. Acta 973, 355-382] were studied. 2. Cyclosporin (1 microM) had no significant effect on the swelling induced by butyrate, bongkrekic acid or Ca2+ at concentrations of less than 0.3 microM. 3. At higher [Ca2+] (greater than 0.3 microM), swelling became progressively inhibited by cyclosporin, although the increase in matrix PPi was slightly greater in the presence than in the absence of cyclosporin. 4. Titration with cyclosporin indicated that there are 128 pmol of relevant cyclosporin-binding sites per mg of mitochondrial protein, with a Ki of about 5 nM. 5. The decrease in light-scattering by hepatocytes induced by butyrate [Davidson & Halestrap (1988) Biochem. J. 254, 379-384] was unaffected by cyclosporin, whereas that induced by vasopressin was inhibited by 20-30% without a significant change in cellular PPi content. 6. It is suggested that there are two mechanisms for the increase in mitochondrial volume induced by Ca2+: a PPi-mediated mechanism that is insensitive to cyclosporin and an additional Ca2(+)-mediated effect that is inhibited by cyclosporin. The nature of these pathways and their inter-relationship is discussed in the following paper [Halestrap & Davidson (1990) Biochem. J. 268, 153-160].

Animals↗
PubMed1998

Butyrate-stable monosaccharide derivatives induce maturation and apoptosis in human acute myeloid leukaemia cells.

The rapid degradation and subsequent lack of efficacy of n-butyric acid in vivo has been improved by the synthesis of monosaccharide stable pro-drugs of butyric acid. We studied the effects of D1 (O-n-butanoyl-2,3-O-isopropylidene-alpha-D-mannofuranoside), G1 (1-O-n-butanoyl-D,L-xylitol), and F1 (1-O-n-butanoyl 2,3-O-isopropylidene-D,L-xylitol) on the maturation and proliferation of AML cell lines HL 60 and FLG 29.1 and of purified blast cells from 10 cases of de novo acute myeloid leukaemia (AML). AML cell maturation was measured by surface antigen expression, morphology and cytochemistry. Toxicology in mice was also evaluated (DL50 1000 mg/kg). In HL 60 cells G1 and D1 increased the expression of CD15 and CD11a (presenting 62% of promyelo-metamyelocytes), and in 7/10 cases of primary AMLs that of CD11a, CD11b, CD15, and myeloperoxidase. D1, G1 and F1 induced a dose-dependent inhibition of tritiated thymidine uptake. Apoptosis (evaluated by flow cytometry and agarose gel electrophoresis) was induced in AML blasts by D1 and F1 (79% and 94% respectively for HL 60 cells) and, with less effect, by G1 (27%). The persistence of maturative and apoptotic activity in these new pro-drugs of butyric acid, hydrolysed only inside the tumour cell, suggests a possible use in differentiation therapy of myelodysplastic syndromes and AMLs.

Acute Disease↗
PubMed1984

Activation of a chicken embryonic globin gene in adult erythroid cells by 5-azacytidine and sodium butyrate.

Adult White Leghorn chickens were rendered anemic by injection with 1-acetyl-2-phenylhydrazine and then treated with parenteral 5-azacytidine, and levels of embryonic globin RNA in circulating reticulocytes were measured. A very small but detectable amount of correctly initiated embryonic p-type globin RNA was detected in reticulocytes from birds treated with 5-azacytidine, while none was detected in reticulocytes from those receiving only phenylhydrazine or phenylhydrazine plus 1-beta-D-arabinofuranosylcytosine (cytosine arabinonucleoside). An attempt to increase embryonic globin RNA induction by treatment with parenteral sodium butyrate after 7 days of 5-azacytidine administration resulted in a 5- to 10-fold increase in the level of embryonic globin RNA. However, sodium butyrate did not induce embryonic gene expression when given alone or after treatment with cytosine arabinonucleoside. Sodium butyrate treatment also caused a DNase I-hypersensitive site to be exposed at the 5' end of the rho-globin gene only after 5-azacytidine induced demethylation of several CpG sites in and around the gene. The implications of this model of gene activation in vivo are discussed in the context of multistep gene regulation.

Animals↗
PubMed1996

Effect of HIV type 1 Tat protein on butyric acid-induced differentiation in a hematopoietic progenitor cell line.

The trans-activator protein (Tat) of HIV-1 plays an important role in viral pathogenesis. Since Tat has been shown to alter expression of a number of host cellular genes, we have investigated the role of Tat in modulating gene expression and differentiation in hematopoietic progenitor cells. Tat protein was introduced in K562 cells, a human hematopoietic progenitor cell line, by either scrape-loading onto HeLa (HL)-tat cells or direct electroporation of an affinity-purified glutathione S-transferase (GST)-Tat fusion protein. Under these conditions, butyric acid-induced hemoglobin production in K562 cells was suppressed by 65 and 52%, respectively. However, coculturing with wild-type HeLa cells or electroporation with the control GST protein did not decrease hemoglobin production. To confirm the presence of bioactive Tat protein within K562 cells, the cells were transiently transfected with a pHIV/LTR-CAT prior to the introduction of Tat. A 30- to 40-fold induction in CAT gene expression was observed in the transfected K562 cells, which were either cocultured with HL-tat or were electroporated with GST-Tat. Simultaneous transient transfection of K562 cells with a TAR expression plasmid, to compete for the availability of Tat protein, significantly downregulated the HIV LTR trans-activation by Tat. In addition, overexpression of the TAR RNAs in K562 cells was able to downregulate the suppressive effect of Tat on butyric acid-induced differentiation. RT-PCR analysis of the total RNAs isolated from these cells demonstrated that Tat protein suppressed the butyric acid-induced gamma-globin gene expression by an average of 54% without affecting the level of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNAs. These data indicate that the viral Tat protein plays a significant role in abrogating erythroid differentiation in K562 cells.

Butyrates↗
PubMed1996

Importance of glycolipid synthesis for butyric acid-induced sensitization to shiga toxin and intracellular sorting of toxin in A431 cells.

The human epidermoid carcinoma cell line A431 becomes highly sensitive to Shiga toxin upon treatment with butyric acid. This strong sensitization (> 1000-fold) is accompanied by an increase in the fraction of cell-associated toxin transported to the Golgi apparatus and to the endoplasmic reticulum (ER). Furthermore, our previous work showed that the length of the fatty acyl chain of Gb3, the Shiga toxin receptor, also was changed (longer fatty acids). We have not investigated the importance of this change by testing whether glycolipid synthesis is required for the changed intracellular sorting and the toxin sensitivity. We demonstrate here that inhibition of glycosphingolipid synthesis by inhibition of N-acyltransferase with fumonisin B1, by inhibition of glucosylceramide synthetase by PDMP or PPMP, or by inhibition of serine palmitoyl transferase by beta-fluoroalanine, inhibited the butyric acid-induced change in sensitivity and the increase in the fraction of cell-associated Shiga toxin transported to the Golgi apparatus and the ER. The block in butyric acid-induced sensitization caused by beta-fluoroalanine could be abolished by simultaneous addition of sphinganine or sphingosine. Thus, the data suggest that the fatty acyl chain length of glycosphingolipids is important for intracellular sorting and translocation of Shiga toxin to the cytosol.

Acyltransferases↗
PubMed1987

Effect of butyric acid on 12-O-tetradecanoylphorbol-13-acetate-(TPA) induced mouse skin ornithine decarboxylase (ODC).

Butyric acid was topically applied on the interscapular region of Swiss albino mice before and after application of 12-O-tetradecanoylphorbol-13-acetate (TPA) in various doses and at different time intervals. Skin taken from the painted area, 4 h after TPA application, was subjected to ornithine decarboxylase (ODC) enzyme estimation. It was found that butyric acid inhibited the TPA-induced mouse skin ODC activity. The effect was dependent on the dose and duration of the butyric acid application.

Animals↗
PubMed1996

Comparison of the effects of Shiga-like toxin 1 on cytokine- and butyrate-treated human umbilical and saphenous vein endothelial cells.

To examine the reported heterogeneity of endothelial cells to Shiga-like toxin 1 (Stx1), the responses of human umbilical (HUVEC) and saphenous (HSVEC) vein endothelial cells to cytokines, butyrate, and toxin were compared. Untreated HSVEC were generally more susceptible than were HUVEC to Stx1; pretreatment of either cell with lipopolysaccharide, interleukin-1 beta, or tumor necrosis factor-alpha enhanced Stx1 toxicity. Dexamethasone alone increased total globotriaosylceramide (Gb3) content and toxin binding but inhibited cytokine-enhanced cytotoxicity, whereas the differentiation agent, sodium butyrate, increased both Gb3 content and cytotoxicity responses to Stx1, most prominently in HSVEC. Stx1 toxicity directly correlated with the release of von Willebrand factor from HSVEC but not from HUVEC. Thus, HUVEC and HSVEC exhibit distinctive responses to Stx1, cytokines, and butyrate. This suggests the need for caution in extrapolating from in vitro studies utilizing one endothelial cell type to in vivo events during pathogenesis of Stx-mediated thrombotic microangiopathies.

Bacterial Toxins↗
PubMed1993

Acute metabolic and hormonal effects of intravenously administered sodium n-butyrate in untreated and alloxan-diabetic sheep.

Experimental diabetes was induced in 4 wethers of the Mutton Merino breed by intravenous injection of alloxan (75 mg.kg-1) in order to determine its impact on plasma glucose, immunoreactive insulin, free fatty acids (FFA), cholesterol, phospholipids, triglycerides, D-(-)-3-hydroxybutyrate (D-3-HB), bilirubin and aspartate aminotransferase (ASAT) as well as on the changes of these parameters brought about by an intravenous infusion of sodium n-butyrate (1 mmol.kg-1). Alloxan administration caused a significant elevation of plasma glucose, FFA, triglycerides, cholesterol, phospholipids, D-3-HB and bilirubin and a decrease of the level of immunoreactive insulin. The increase in glucose level brought about by a bolus injection of sodium n-butyrate in untreated sheep did not appear in alloxanized animals. Thus, it is suggested that the lack of hyperglycaemic response in diabetic sheep was due to the absence of liver glycogen stores. Unexpectedly in alloxan-diabetic sheep, a decrease in the plasma level of FFA occurred after the administration of sodium n-butyrate. Therefore, it may be assumed that beside insulin other factors may contribute to the decrease of FFA under these conditions.

Alloxan↗
PubMed1997

Emergence of an irreversible differentiated subclone from the poorly differentiated ovarian adenocarcinoma cell line AMOC-2 treated with sodium butyrate.

OBJECTIVE: To cast light on the capacity of an ovarian adenocarcinoma to undergo irreversible cellular differentiation, we established clonal cell lines from cultured ovarian carcinoma cells treated with sodium butyrate and examined their phenotypic changes. METHODS: The poorly differentiated ovarian carcinoma cell line AMOC-2 was exposed to 2 mM sodium butyrate for 30 days, and clonal cell lines were established by a dilution plating technique. RESULTS: Five clonal cell lines were established. One of them had a longer doubling time and lower plating efficiency than the parental clone, also demonstrating stronger expression of vimentin and 56 kD cytokeratin. This clone became columnar with pronounced polarity, formed gland-like structures when cultured in collagen gels, and exhibited no tumorigenicity, in contrast to the parental clone. CONCLUSION: Sodium butyrate treatment of AMOC-2 cells can cause phenotypic changes reminiscent of maturation in the Müllerian duct, endocervix, and/or endometrium.

Adenocarcinoma↗
PubMed1997

Bacterial metabolites sodium butyrate and propionate inhibit epithelial cell growth in vitro.

The structural and functional barrier preventing the free advancement of microbial plaque subgingivally along the tooth surface is formed by the junctional epithelial (JE) cells directly attached to the tooth (DAT cells). The mechanism leading to degeneration of the DAT cells is not known. In the present study we examined the possible role of short chain fatty acids (SCFAs) on epithelial cells by making use of 2 epithelial cell cultures (HaCaT and ERM) and an explant culture model of human JE. The SCFAs butyrate and propionate were used in concentrations found in human plaque and gingival crevicular fluid (0.25-16.0 mM). The SCFAs had no effect on primary cell adhesion nor on the epithelial attachment apparatus (EAA). By contrast, even 0.25 mM of butyrate significantly retarded epithelial cell growth. Similar effects with propionate were first observed at concentrations higher than 1.0 mM. The retardation of epithelial cell growth was found to be due to inhibition of cell division. Furthermore, after butyrate treatment dense accumulations of intermediate filaments and cytoplasmic vacuolization were characteristically seen in cells adjacent to cells of normal appearance. This suggests that some cells of the growing epithelial cell population are more sensitive to the SCFAs than others, and agrees with previous reports on the DAT cells of periodontally-involved teeth in vivo. The results suggest that SCFAs are microbial factors that play a role in the initiation and progression of periodontal pocket formation by impairing epithelial cell function rather than having a direct effect on the EAA.

Analysis of Variance↗
PubMed1987

Transport of substrates and metabolites and their effect on cell metabolism (in butyric-acid and methylotrophic fermentations).

The two components, delta pH and delta psi, of the membrane protonmotive force (delta p) effect and are affected by the transport of many substrates and metabolites. Because the integrity (or restoration) of the delta p requires the expenditure of metabolic energy, such transport processes affect the overall cell bioenergetics. However, the transport or high concentrations of certain substrates and metabolites can have more serious effects on cell metabolism because they partially or completely abolish either or both the delta pH and delta psi. If the cells cannot eventually restore the collapsed component(s) of the delta p, complete growth inhibition and cell death become inevitable. In the butanol/acetone fermentation of Clostridium acetobutylicum, the transport and the presence of key metabolites (acetic and butyric acids, and butanol) have serious and some necessary effects on the delta p. Acetic and butyric acids act as uncouplers of the delta pH, thereby reducing the internal pH. Using other acid uncouplers (such as acetoacetate, which is metabolized by the cells, or FCCP, which is not metabolized by the cells), we found that a lower pHo combined with the metabolic-energy drain of the uncoupling effect and high internal acid concentrations are implicated in the mechanism(s) of solventogenesis. Thus, the production or presence (or both) of the two acids (acetic and butyric) is beneficial to the initiation of solvent production. The transport mechanisms of CH3OH, CH2O, and HCOOH in obligate CH3OH utilizers (methylotrophs) were also discussed in detail. We showed that CH3OH is actively transported by the cells at the expense of metabolic energy and that its transport significantly affects the dynamics of continuous bioreactors. The accumulation of CH2O was found to be driven by the membrane delta p. Finally, formate was accumulated by the delta pH according to the general transport mechanism of short-chain fatty acids. The inhibition of growth by formate was explained by its uncoupling effect on the cells. Growth inhibition by CH3OH appeared to be related to the severe reduction of the membrane delta pH and cell pHi by relatively low CH3OH concentrations.

Biological Transport↗
PubMed1987

Chemical inducers of differentiation, dimethylsulfoxide, butyric acid, and dimethylthiourea, induce selective ultrastructural patterns in B16 melanoma cells.

The morphology and ultrastructure of B16 melanoma cells was examined after treatment of the cells with the chemical inducers of differentiation dimethylsulfoxide (DMSO), butyric acid, and dimethylthiourea (DMTU). The treated B16 melanoma cells seemed to be enlarged and more flattened, and to possess dendrite-like structures as revealed by scanning electron microscopy. The main ultrastructural features, depicted by transmission electron microscopy in DMSO-treated B16 cells were: a marked increase in melanin granules, migration of the melanin granules to the dendrites, and appearance of melanosome aggregates. Butyric acid did not induce melanin biosynthesis; however, it stimulated rough endoplasmic reticulum (RER) formation all over the cytoplasm. The DMTU-treated cells also showed a well developed RER accompanied by early stages of melanosomes and melanin granules. The increase in the endoplasmic reticulum was also reflected by enhancement of NADPH cytochrome c reductase activity, an enzymatic marker of the endoplasmic reticulum. The mitochondria in the DMTU-treated cells were swollen with disrupted cristae. The results indicate that DMSO, butyric acid, and DMTU induce different ultrastructural patterns in B16 melanoma cells. These findings correlate with the biochemical alterations induced in melanoma cells by these agents.

Animals↗
PubMed1982

Alteration in the simian virus 40 maturation pathway after butyrate-induced hyperacetylation of histones.

The role of histone acetylation in the replication and maturation pathways of simian virus 40 was assessed. Histones were hyperacetylated by briefly exposing infected cells to sodium butyrate. Viral DNA in cells exposed to butyrate was found to reenter replication to a greater extent and mature to the previrion form to a lesser extent than viral DNA in control cells. Previrions formed in the presence of butyrate had altered sedimentation properties. These data suggest that increased acetylation of histones is not the signal for removal of DNA from the pool of molecules available for replication. It appears, in fact, that hyperacetylation retards entry into and progression along the maturation pathway.

Acetylation↗
PubMed1987

Effect of cerulenin and sodium butyrate on chitin synthesis in Candida albicans.

Experiments were conducted to gain insight concerning the mechanism(s) whereby cerulenin and sodium butyrate affect chitin synthesis in Candida albicans. In vitro studies with isolated membrane-bound chitin synthase from C. albicans, strain 4918, showed that neither agent affected the level of either unactivated or trypsin-activated enzyme activity. Subsequent studies utilizing protoplasts revealed that early in the cell wall regeneration process, cells treated with cerulenin or butyrate synthesized chitin at a rate equal to untreated controls, as measured by the incorporation of [3H]-N-acetylglucosamine (GlcNAc) into acid-alkali insoluble material. However, after 40 min of incubation, the incorporation of [3H]GlcNAc into chitin is reduced in cells treated with either agent. On the other hand, samples taken during the same time intervals and analyzed by flow cytometry suggested that the amount of chitin synthesis in treated and untreated cells was identical. A marked decrease in fluorescence was observed in similar experiments using polyoxin D, a direct inhibitor of chitin synthase activity. Experiments that measured uptake of [3H]GlcNAc into both whole cells and protoplasts demonstrated that cerulenin and butyrate had no effect on the transport of the chitin precursor.

Antifungal Agents↗
PubMed1982

Effects of butyrate on ouabain-sensitive respiration of hamster brown adipocytes.

Brown adipose tissue is an important site of cold-induced nonshivering thermogenesis in many mammals. The plasma membrane-bound Na+-K+-ATPase has been shown to be significantly involved in this thermogenesis although its exact role is unknown at present. Evidence that coupling of oxidative phosphorylation to electron transport may become loosened during thermogenesis has prompted an investigation of potential roles of the Na+-K+ pump that would be compatible with altered respiratory coupling. One such role is that of modulating norepinephrine (NE)-induced lipolysis and hence provision of free fatty acids to the mitochondria. Under such conditions, inhibition of the pump would reduce NE-induced respiration by limiting substrate availability. If, in fact, the primary role of the pump in NE-induced thermogenesis is to facilitate substrate availability, provision of exogenous substrate should bypass this involvement and ameliorate the ouabain inhibition of respiration. In the present study, this possibility was examined by determining the effect of an exogenous substrate, butyrate, on the contribution of the Na+-K+ pump to NE-stimulated respiration of isolated hamster brown adipocytes. Although exogenous butyrate was able to serve as a substrate for brown adipocyte respiration, its presence had no significant effect on the ouabain sensitivity of NE-induced rates of oxygen consumption. That is, ouabain (1 mM) inhibited the NE-evoked thermogenesis of the adipocytes by 77.7 +/- 6.5% in the absence of butyrate (2 mM) and by 73.4 +/- 9.9% in its presence. It appears, therefore, that the contribution of the Na+-K+ membrane pump to brown fat thermogenesis does not simply reflect modulation of NE-evoked lipolysis.

Adipose Tissue, Brown↗
PubMedDate not supplied

Effects of deoxycholic acid and butyrate on mucosal prostaglandin E2 release and cell proliferation in the human sigmoid colon.

BACKGROUND: A high-fat, low-fiber diet resulting in increased excretion of fecal secondary bile acids is regarded as a major risk factor for colon cancer. Incubation of human colonic biopsies with the secondary bile acid deoxycholic acid (DCA) leads to hyperproliferation with expansion of the proliferative zone, ie, a biomarker of increased cancer risk. Antiproliferative effects on various colon cancer cell lines, however, were reported for butyrate (BUT), a fermentation product of dietary fiber. METHODS: In the following in vitro study we incubated biopsies from the normal sigmoid colon of 12 patients (age 55.8 +/- 3.6 years) with 5 microM DCA or a combination of 5 microM DCA plus 10 mM BUT (DCA/BUT) and determined epithelial proliferation by bromodeoxyuridine immunohistochemistry. As a possible mediator for the DCA effects on colonic cell proliferation, mucosal prostaglandin E2 (PGE2) release into the incubation medium was measured by 125I-PGE2 radioimmunoassay. RESULTS: Incubation with DCA alone revealed a significantly higher labeling index for the whole crypt (.17 vs .11, p < .01) and for the upper 40% of the crypt (.05 vs .01, p < .01) compared with DCA/BUT. Mucosal PGE2 release during DCA/BUT incubation showed a trend toward lower values compared with DCA incubation (357.07 vs 434.29 pg/mg per hour; p = .07). CONCLUSION: The results indicate a normalization of DCA-induced hyperproliferation of colonic epithelium by butyrate that is not clearly mediated by PGE2. Considering that nutrition affects the luminal concentrations of DCA and butyrate, our findings may have implications for colonic carcinogenesis.

Bromodeoxyuridine↗
PubMed1992

Effects of the butyric short-chain fatty acid on the bioelectric brain activity of rabbits.

The effects of the butyric short-chain fatty acid, an agent with proved comagenic action, on the bioelectric brain activity of rabbits was studied. In all monopolar leads, paroxysms were recorded which manifested themselves 15 to 30 minutes after the infusion of butyrate. The analysis used F2 exogenic prostaglandins and indomethacin, an inhibitor of prostaglandin synthesis. It was found that the system for prostaglandin synthesis plays a role in the effects of butyrate.

Animals↗