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PubMed2006

Sodium butyrate-mediated Sp3 acetylation represses human insulin-like growth factor binding protein-3 expression in intestinal epithelial cells.

OBJECTIVES: Butyrate concentrations in the gastrointestinal tract vary greatly with age. In intestinal epithelial cells, butyrate enhances gene transcription by increasing histone acetylation, rendering the nucleosome open to transcription factors. However, it inhibits human insulin-like growth factor binding protein (hIGFBP)-3 expression. We therefore hypothesized that butyrate also acts by regulating transcription factor acetylation. METHODS: Gene regulation was examined in Caco-2 cells. RNA stability was measured after interruption of transcription. The activity of deletion mutations of the hIGFBP-3 promoter was examined in reporter assays. Transcription factor binding to promoter DNA was analyzed. RESULTS: Butyrate did not increase the transcription of a repressor because it inhibited hIGFBP-3 mRNA in the absence of protein synthesis. Nor did butyrate decrease the stability of hIGFBP-3 mRNA. Analysis of the hIGFBP-3 promoter demonstrated a butyrate-response element that included the binding sites for p300 and Sp1/Sp3. Transfection of Caco-2 cells with E1A, an inhibitor of p300 acetyltransferase activity, reversed the butyrate-induced repression of hIGFBP-3. Because Sp3 represses the initiation of transcription, we studied whether butyrate induced Sp3 acetylation. Electrophoretic mobility shift assays of nuclei extracted from Caco-2 cells treated with 5 mmol/L butyrate demonstrated an extra, heavier band in addition to the Sp3-DNA binding in untreated cells. This corresponded to a protein, detected only in butyrate treated cells, that was identified both by an anti-Sp3 antibody and by an anti-acetyl lysine antibody. CONCLUSIONS: This study demonstrates that butyrate increases the acetylation of a nonhistone protein, Sp3, catalyzed by p300 acetyltransferase activity.

Acetylation↗
PubMed2006

Does butyrate protect from colorectal cancer?

Butyrate, the four-carbon fatty acid, is formed in the human colon by bacterial fermentation of carbohydrates (including dietary fiber), and putatively suppresses colorectal cancer (CRC). Butyrate has diverse and apparently paradoxical effects on cellular proliferation, apoptosis and differentiation that may be either pro-neoplastic or anti-neoplastic, depending upon factors such as the level of exposure, availability of other metabolic substrate and the intracellular milieu. In humans, the relationship between luminal butyrate exposure and CRC has been examined only indirectly in case-control studies, by measuring fecal butyrate concentrations, although this may not accurately reflect effective butyrate exposure during carcinogenesis. Perhaps not surprisingly, results of these investigations have been mutually contradictory. The direct effect of butyrate on tumorigenesis has been assessed in a number of in vivo animal models, which have also yielded conflicting results. In part, this may be explained by methodological differences in the amount and route of butyrate administration, which are likely to significantly influence delivery of butyrate to the distal colon. Nonetheless, there appears to be some evidence that delivery of an adequate amount of butyrate to the appropriate site protects against early tumorigenic events. Future study of the relationship between butyrate and CRC in humans needs to focus on risk stratification and the development of feasible strategies for butyrate delivery.

Animals↗
PubMed2001

Butyric acid-induced T-cell apoptosis is mediated by caspase-8 and -9 activation in a Fas-independent manner.

Our previous study demonstrated that butyric acid, an extracellular metabolite of periodontopathic bacteria, induced apoptosis in murine thymocytes, splenic T cells, and human Jurkat cells. In this study, we examined whether CD95 ligand-receptor interaction is involved in butyric acid-induced T-cell apoptosis. Flow cytometry analysis indicated that expression of Fas in Jurkat and T cells from peripheral blood mononuclear cells was not affected by butyric acid treatment. Furthermore, the expression of Fas and FasL protein in Western blotting was not affected by butyric acid treatment. Coincubation with blocking anti-Fas antibodies prevented Fas-induced apoptosis but not butyric acid-induced apoptosis. Anti-FasL antibodies also did not prevent butyric acid-induced apoptosis at any dose examined. Although cytotoxic anti-Fas antibody affected butyric acid-induced apoptosis, a synergistic effect was not seen. Time-dependent activation of caspase-8 and -9 was recognized in butyric acid- as well as Fas-mediated apoptosis. IETD-CHO and LEHD-CHO, specific inhibitors of caspase-8 and -9, respectively, completely blocked Fas-mediated apoptosis and partially prevented butyric acid-induced apoptosis. These results suggest that the Fas-FasL interaction is not involved in butyric acid-induced apoptosis and that caspase-8 and -9-dependent apoptosis plays an important role in butyric acid-induced apoptosis, as well as Fas-induced apoptosis.

Adult↗
PubMed2000

Butyrate and trichostatin A effects on the proliferation/differentiation of human intestinal epithelial cells: induction of cyclin D3 and p21 expression.

BACKGROUND: Sodium butyrate, a product of colonic bacterial fermentation, is able to inhibit cell proliferation and to stimulate cell differentiation of colonic epithelial cell lines. It has been proposed that these cellular effects could be linked to its ability to cause hyperacetylation of histone through the inhibition of histone deacetylase. AIM: To analyse the molecular mechanisms of butyrate action on cell proliferation/differentiation and to compare them with those of trichostatin A, a well known inhibitor of histone deacetylase. METHODS: HT-29 cells were grown in the absence or presence of butyrate or trichostatin A. Cell proliferation and cell cycle distribution were studied after DNA staining by crystal violet and propidium iodide respectively. Cell cycle regulatory proteins were studied by western blot and reverse transcription-polymerase chain reaction. Cell differentiation was followed by measuring brush border enzyme activities. Histone acetylation was studied by acid/urea/Triton acrylamide gel electrophoresis. RESULTS: Butyrate blocked cells mainly in the G(1) phase of the cell cycle, whereas trichostatin A was inhibitory in both G(1) and G(2) phases. Butyrate inhibited the mRNA expression of cyclin D1 without affecting its protein expression and stimulated the protein expression of cyclin D3 without affecting its mRNA expression. Trichostatin A showed similar effects on cyclin D1 and D3. Butyrate and trichostatin A stimulated p21 expression both at the mRNA and protein levels, whereas their effects on the expression of cyclin dependent kinases were slightly different. Moreover, butyrate strongly stimulated the activity of alkaline phosphatase and dipeptidyl peptidase IV, whereas trichostatin A had no effect. Finally, a six hour exposure to butyrate or trichostatin A induced histone H4 hyperacetylation. At 15 and 24 hours, histone H4 remained hyperacetylated in the presence of butyrate, whereas it returned to control levels in the presence of trichostatin A. CONCLUSIONS: The data may explain how butyrate acts on cell proliferation/differentiation, and they show that trichostatin A does not reproduce every effect of butyrate, mainly because of its shorter half life.

Acetylation↗
PubMed1999

Induction of apoptosis by monosaccharide butyrate stable derivatives in chronic lymphocytic leukemia cells.

BACKGROUND AND OBJECTIVE: Different therapeutic approaches are needed to restore apoptotic mechanisms in CLL cells, as present ones are not successful. We assessed the apoptotic effects of stable butyrate derivatives on CLL lymphocytes: in these molecules a mannose molecule is bound as ester to one-five butyrate moieties, conferring pharmacological stability to the pro-drugs which are able to induce apoptosis in primary AML blasts. DESIGN AND METHODS: Peripheral blood samples obtained from 17 patients with typical B-CLL were cultured in the presence of 0.5-1mM D1 (O-n-butanoyl-2, 3-O-isopropylidene-a-D-mannofuranoside), F1 (1-O-n-butanoyl-2, 3-O-isopropylidene-D,L-xylitol) and G1 (1-O-n-butanoyl-D,L-xylitol) derivatives for 4 days and equimolar sodium butyrate as comparison. After culture, apoptosis was evaluated by cell morphology, cellular DNA content, pattern of DNA fragmentation, annexin V exposure on cell membrane, and cell cycle parameters. Bcl2, bax, and fas oncogene expression were also evaluated by the APAAP method. RESULTS: The addition to cell cultures of D1 or F1 or G1 butyrate monosaccharides as well as sodium butyrate 0.5 and 1 mM determined to different extents an increase in the percentage of apoptotic cells in all CLL samples, relatively to the method and butyrate molecule added in culture. Heterogeneity in CLL cell sensitivity to the three butyrates was observed. Up to 60-68% apoptotic bodies were present in treated cultures after exposure to D1 0.5-1 mM, 60-72% after F1 0.5-1 mM and 48-60% after G1 0.5-1 mM. Comparison of untreated versus treated cultures yielded important significance (p< 0.001). At DNA content analysis, analyzed by flow cytometry, apoptotic events were accounting for up to 70-77% of D1-treated and 68-74% of F1-treated CLL cells at 0.5 and 1 mM concentrations (p= 0. 0001, vs controls 0-39%), and for 72-81% of G1 (0.5-1 mM) treated cells (overall, p=0.005). Cell cycle parameters were not altered by addition of butyrates, but expression of Annexin V was greatly enhanced. In a limited number of CLL cases fas, bcl2/bax ratio was analyzed and found unmodified. INTERPRETATION AND CONCLUSIONS: Monosaccharide butyrate stable derivatives are potent inducers of primary CLL cell apoptosis, both in untreated and alkylating agent pre-treated cases. Our results suggest that the apoptotic pathways elicited by butyrate in CLL lymphocytes are direct, specific and most probably do not involve bcl2/bax. Pro-apoptotic agents like the stable monosaccharide butyrate derivatives here studied could bring more insights into CLL biology and resistance to apoptosis, and possibly originate alternative treatments for CLL.

Aged↗
PubMed2002

[The promoter effects of sodium butyrate on the malignant transformation of the immortalized esophageal epithelium induced by human papillomavirus].

OBJECTIVE: Study on the promoter effects of sodium butyrate in high or low dosages on carcinogenesis process, based on the immortalization of human fetal esophageal epithelium induced by human papillomavirus (HPV) 18E(6)E(7) genes. METHODS: The immortalized esophageal epithelium SHEE was treated with high concentration of the sodium butyrate (80 mmol/L) and then with low concentration (5 mmol/L) for 8 weeks respectively. The cells were cultured continuously without sodium butyrate for 14 weeks. The morphology, proliferation and apoptosis of the cells were studied by phase contrast microscopy, immunohistochemistry and flow cytometry. The dead and the viable cells were assayed by fluorescent microscopy with Hoechst 33342 and Propidium iodide staining. Tumorigenesis of the cells was assessed by soft agar colony formation and by transplantation of cells into nude mice and SCID mice. RESULTS: When cells were exposed to high concentration of sodium butyrate, cell death was increased leaving few live cells. When cells were cultured in the medium with low concentration of sodium butyrate, the first proliferative stage appeared. Removal of the butyrate caused the cell to enter a crisis stage with a long doubling time resembling senescent cells. After the crisis stage, the cells progressed to the second proliferation stage with continuous replication and atypical hyperplasia. At the end of the second proliferative stage, carcinogenesis of the cells appeared with large colonies in soft-agar and tumor formation in transplanted SCID mice and nude mice. CONCLUSIONS: The malignant change of the immortalized epithelium by the effects of sodium butyrate is the consequence of a two-stage mortality mechanism: cells death by butyrate cytotoxicity and cell crisis by abrogation of sodium butyrate. These data reveal that in high dosage, sodium butyrate induces cell death and in low dosage, it induces cell proliferation, which emphasizes the importance of butyrate as a promotor of carcinogenesis.

Animals↗
PubMed1986

Synergistic effects of butyrate on platelet responses to arachidonate, A23187, PGE1, and forskolin.

With eukaryotic cells, butyrate is known to induce a series of morphological and biochemical changes that mimic cellular differentiation. With platelets, we have found that butyrate (10 mmol/L) caused an approximately threefold increase in sensitivity to calcium ionophore A23187 and arachidonate. Maximum aggregation was observed at agonist concentrations of 3 mumol/L and 170 mumol/L, respectively, as compared with required concentrations of 10 mumol/L and 400 mumol/L in the absence of butyrate. Similar effects were seen with isobutyric acid, and about one-half the effect was shown with valerate and caproate, but lower homologues showed no synergistic effect. No ultrastructural changes were observed in platelets incubated with butyrate, and the aggregation effects were reversible and returned to normal on removal of butyrate. Membrane fluidity was unchanged by butyrate as measured by changes in the fluorescence depolarization of diphenylhexatriene. Butyrate caused a 60% to 70% increase in the uptake of 3H-arachidonate. Butyrate also potentiated the inhibition of platelet function by prostaglandin E1 and forskolin and uptake of 3H-forskolin was increased approximately 20%. In contrast, platelet response to other agonists (ADP, epinephrine, collagen, thrombin, and platelet-activating factor) was essentially unaffected by butyrate. These results suggest that butyrate may increase the uptake of certain hydophobic agonists and antagonists by platelets. Similar mechanisms for uptake of endogenous effectors may explain the response of eukaryotic cells to butyrate in culture.

Alprostadil↗
PubMed1996

Different effects of cyclic AMP and butyrate on eosinophilic differentiation, apoptosis and bcl-2 expression of a human eosinophilic leukemia cell line, EoL-1.

A human eosinophilic leukemia cell line, EoL-1, stopped proliferating at the G1 phase, differentiated into eosinophilic granule-containing cells, and died by apoptosis when stimulated with dibutyryl cyclic AMP (dbcAMP). To clarify the effects of dbcAMP, the effects of butyrate and cAMP-increasing reagents, prostaglandin E2 (PGE2) and forskolin, on EoL-1 cellular differentiation and apoptosis were examined and compared. PGE2 and forskolin but not butyrate induced differentiation to eosinophilic granule-containing cells, suggesting that cAMP played a primary role in eosinophilic differentiation of EoL-1 cells. PGE2, forskolin and butyrate, when used alone, did not induce apoptosis of EoL-1 cells significantly at the concentrations used, but sequential stimulation of EoL-1 cells with the cAMP-increasing reagents and butyrate showed that butyrate induced further maturation and apoptosis of cAMP-induced eosinophilic granule-containing cells. These results showed that cAMP and butyrate have different effects on eosinophilic differentiation and apoptosis of EoL-1 cells. The cAMP-increasing reagents and butyrate also showed different effects on expression of members of the bcl-2 family; PGE2 decreased bcl-2 and bax levels, whereas butyrate increased the bcl-2 level. PGE2 or PGE2+butyrate, but not butyrate alone, induced bcl-XS expression. EoL-1 cells constitutively expressed Fas and anti-Fas antibody induced EoL-1 cell death, but the Fas/Fas ligand system was not involved in dbcAMP-induced EoL-1 cell apoptosis. The EoL-1 cell line is thus a useful model in which to examine differentiation and apoptosis of eosinophilic leukemia cells.

Apoptosis↗
PubMed1997

Butyrate inhibits deoxycholate-induced increase in colonic mucosal DNA and protein synthesis in vivo.

PURPOSE: Crypt surface hyperproliferation is an intermediate biomarker of colon cancer risk. In vitro studies indicate that the short-chain fatty acid and antineoplastic agent butyrate may reverse the crypt surface hyperproliferation induced by the secondary bile acid and tumor promoter, deoxycholate. We hypothesized that butyrate may reverse deoxycholate-induced crypt surface proliferation in vivo. METHODS: Thirty-one Sprague-Dawley rats (250-300 g) underwent surgical isolation of the colon and 24-hour luminal instillation of either sodium chloride, butyrate, deoxycholate, or butyrate plus deoxycholate (all solutions, 2 ml; pH 7; total sodium = 20 mM). Study variables included colon weight, mucosal DNA, mucosal protein, and proliferating cell nuclear antigen immunohistochemistry, labeling of which was determined in five crypt compartments from base to surface (12 crypts per rat). Labeling indexes were calculated as proliferating cell nuclear antigen immunohistochemistry-labeled cells divided by total counted cells in the whole colonic crypt and each of five crypt compartments. The phi(h) value (an index of premalignant risk) was calculated as the ratio of labeled cells in the two surface compartments divided by the total labeled cells. RESULTS: Deoxycholate significantly increased colon wet weight, mucosal protein, total crypt labeling indexes, crypt surface labeling indexes, and the phi(h) value and raised the mucosal DNA content. Butyrate alone slightly reduced total mucosal DNA and protein content. The combination of butyrate plus deoxycholate significantly decreased mucosal DNA and tended to reduce mucosal protein compared with deoxycholate alone. In contrast to prior in vitro findings, butyrate plus deoxycholate did not reverse the deoxycholate-induced surface hyperproliferative changes as measured by proliferating cell nuclear antigen labeling. CONCLUSIONS: Because co-treatment with butyrate plus deoxycholate inhibits deoxycholate-induced increases in total mucosal DNA and protein content, we conclude that butyrate may play a role in maintaining the proliferative balance of the colonic mucosa, in vivo. However, co-treatment with butyrate plus deoxycholate does not reverse the deoxycholate-induced increases in colon weight and proliferating cell nuclear antigen labeling indexes under the studied experimental conditions.

Animals↗
PubMed1994

Butyrate, mesalamine, and factor XIII in experimental colitis in the rat: effects on transglutaminase activity.

BACKGROUND/AIMS: Butyrate and factor XIII may improve ulcerative colitis; they also affect tissue and serum transglutaminase levels. We investigated the therapeutic potential of sodium butyrate and factor XIII and the role of transglutaminase during mucosal repair in experimental colitis. METHODS: Rats with induced colitis were treated with sodium butyrate, mesalamine, sodium butyrate plus mesalamine, or saline enemas. Thromboxane B2 was monitored as index of inflammation. In a fifth group, the effectiveness of intravenous Factor XIII was assessed. RESULTS: Sodium butyrate, alone or plus mesalamine, reduced histological activity from 13.7 +/- 1.7 (saline) to 2.5 +/- 1.3 and 2.3 +/- 1.1 (P < 0.01), respectively. Transglutaminase, reduced in the colons of the saline group (783 +/- 157 vs. normal 1800 +/- 192 mU/g; P < 0.01), returned toward normal values in the sodium butyrate or sodium butyrate plus mesalamine groups (1390 +/- 228 and 1226 +/- 172 mU/g, respectively; P < 0.01 vs. saline). Furthermore, sodium butyrate plus mesalamine reduced thromboxane B2 levels by day 5 (0.92 +/- 0.16 vs. saline 1.85 +/- 0.34 ng/mL; P < 0.05). Factor XIII therapy improved the histological picture (2.7 +/- 2.1 vs. saline 13.8 +/- 1.7; P < 0.01) and increased transglutaminase levels both in serum (2.81 +/- 0.11 vs. saline 1.45 +/- 0.09 mU/mL; P < 0.01) and in colon (1503 +/- 127 vs. saline 747 +/- 103). CONCLUSIONS: Sodium butyrate and factor XIII improve colitis, sodium butyrate plus mesalamine reduce early thromboxane B2 synthesis, and transglutaminase(s) plays a role in ulcer healing.

Aminosalicylic Acids↗
PubMed1987

Clinical pharmacology of sodium butyrate in patients with acute leukemia.

Since cancer may be regarded as a disease of differentiation and sodium butyrate induces differentiation of malignant cells in vitro, a study of the clinical pharmacology of sodium butyrate was undertaken. Nine patients with acute myeloid (n = 1), acute monocytic (n = 1), acute myelomonocytic (n = 6) and acute undifferentiated (n = 1) leukemia were treated. Their median age was 52 (range, 27-78) years. Six of the nine patients were pretreated with cytostatic agents. Sodium butyrate was administered i.v. at a dosage of 500 mg/kg/day as continuous infusion over 10 days. A sensitive and reproducible high-performance liquid chromatographic separation was developed after derivatization of sodium butyrate with 2,4'-dibromoacetophenone employing crown ether catalysis. Plasma concentrations and urinary excretion of sodium butyrate were monitored during the 10 days of continuous infusion and for 2 days thereafter. During infusion, plasma concentrations increased 6-fold over the endogenous butyrate level and reached 39-59 microM. The area under the curve of the exogenous butyrate was 384 +/- 50 microM X day (mean +/- S.D.). After the end of infusion, concentrations declined rapidly with a half-life of 6.1 +/- 1.4 min, and reached pretreatment values within 1 hr. The total clearance rate was 83 +/- 12 ml/kg/min and the volume of distribution 738 +/- 245 ml/kg. The excreted amounts of butyrate in the urine were minimal as compared to the infused dose. Although excretion by other organs was not ruled out, it is suggested that the infused sodium butyrate was rapidly metabolized. A significant increase in peripheral blast cells was observed, whereas bone marrow cytologies before and after treatment did not reveal a significant change in blasts. Differential counts of peripheral white blood cells did not show significant changes. No toxicity was encountered. The apparent lack of clinical efficacy may be explained by the low plasma levels of sodium butyrate due to its short half-life in vivo. In comparison, concentrations reported for in vitro studies were at least 10 times higher.

Adult↗
PubMed1997

Lack of butyrate is associated with induction of Bax and subsequent apoptosis in the proximal colon of guinea pig.

BACKGROUND & AIMS: Butyrate stimulates proliferation and suppresses differentiation in normal colonic epithelial cells. Because the involved intracellular signaling mechanisms are unclear, this study investigated certain molecular effects of butyrate. METHODS: Tissue sheets from guinea pig proximal colon were incubated in Ussing chambers in the presence and absence of butyrate. Colonic tissues were examined by scanning and transmission electron microscopy, DNA laddering, Western blots, and immunohistochemistry. RESULTS: After incubation of the colonic mucosa for 150 minutes without butyrate, morphological studies showed massive apoptosis of colonocytes. Simultaneously, these colonocytes exhibited a significant oligonucleosomal DNA fragmentation. In contrast, addition of physiological concentrations of butyrate (10 mmol/L) to colonic sheets showed no detectable DNA fragmentation within 150 minutes. Western blot analysis showed little if any difference in the level of Bcl-2 expression in colonocytes incubated with or without butyrate up to 150 minutes. In contrast, expression of Bax proteins continuously increased after 45 minutes without butyrate and reached a fivefold induction after 150 minutes compared with cells incubated in the presence of butyrate. Moreover, immunohistochemistry using an anti-Bax antibody system showed enhanced labeling of the epithelial colonocytes in the absence of butyrate. CONCLUSIONS: Removal of butyrate induces increased expression of Bax proteins paralleled by rapid apoptosis of colonocytes in vitro.

Animals↗
PubMed1986

Regulation of the rat metallothionein-I gene by sodium butyrate.

Sodium butyrate selectively induces accumulation of metallothionein-I (MT-I) RNA in H4IIE rat hepatoma cells. The induction is rapid; significant elevation in cytoplasmic MT-I RNA can be observed within three hours after exposure to 5 mM butyrate. Maximal levels of MT-I RNA are obtained after eight hours. Butyrate stimulates MT RNA accumulation in the absence of de novo protein synthesis, indicating that MT induction by butyrate is not a distal step in a cascade of gene activation events. Butyrate blocks the induction of tyrosine amino transferase by dexamethasone. In contrast, butyrate and dexamethasone induced MT RNA elevations are additive. Butyrate induced MT-I RNA transcripts initiate at the correct start site. Measurements of the transcriptional activity of the MT-I gene indicate that butyrate stimulates MT-I transcription. The rapid, direct nature of the induction of MT-I by butyrate, combined with the extensive characterization of the metallothionein gene, provide an excellent system in which to study the effects of butyrate on a small, well-defined, responsive region of chromatin.

Animals↗
PubMed1986

Transport of butyric acid in vascularly perfused anuran small intestine: importance of pH and anion transport.

Butyric acid transport was studied in the isolated, vascularly perfused frog small intestine. At luminal butyric acid concentrations of 5-50 mM, absorption was a nonlinear function of the luminal concentration, whereas the relationship of absorption to concentration remained linear at 0-1,000 microM. The most important factor regulating the rate and direction of butyric acid transport was the pH. We used unidirectional flux analysis to determine net transport across the epithelium while the pH of the luminal or vascular compartments was changed. We found a four- to fivefold decrease in butyric acid transport into the portal circulation as the lumen pH was increased from 6.0 to 8.0. The pH of the vascular perfusate influenced the vascular-to-lumen transport of butyric acid in the same proportions. The second important regulatory factor of butyric acid transport was the 4,4'-diisothiocyananostilbene-2,2'-disulfonic acid (DIDS)-sensitive anion transport protein. DIDS added to the lumen at 10(-6) M decreased butyric acid transport by approximately 40% at pH 7.4. DIDS also inhibited butyric acid transport when added to the vascular perfusate or when transport was measured in a vascular-to-lumen direction. We suggest that, at the relatively low pH of the proximal small intestine, butyric acid becomes protonated and lipophilic and is mainly transported directly through the cell membrane. At the more alkaline pH of the distal small intestine butyric acid is in the ionized form and transport by the DIDS-sensitive anion transport protein may predominate.

3-O-Methylglucose↗
PubMed1984

Increased steroid responsiveness during sodium butyrate-induced "differentiation" of HeLa S3 cells.

Pretreatment of HeLa S3 cells with 5 mM sodium n-butyrate markedly enhances cellular responsiveness to the synthetic glucocorticoid dexamethasone, using increased alkaline phosphatase activity as a marker for steroid action. In contrast, dexamethasone pretreatment does not affect the responses of cells to butyrate. Maximal effects of butyrate on steroid responsiveness occur after 2 days of pretreatment. The increased responsiveness of butyrate-pretreated cells to dexamethasone is partially explained by the collection of most cells at a block point in the hormonally responsive portion of the G1 phase of the cell cycle. Cell cycle population effects on steroid responsiveness are lost only gradually over 40 h after the release from butyrate, as cells leave the hormonally responsive late G1 and S phases. In addition to cell cycle population effects, a second, more rapidly reversible effect of butyrate on steroid responsiveness occurs within the late G1 phase itself at the butyrate block point. This second effect is fully and rapidly lost within 10 h after butyrate's removal, a time before the entry of the released cells into S phase. The reversal of butyrate-induced histone hyperacetylation was examined during this 10-h period. Hyperacetylation is lost in less than 2.5 h after butyrate's removal, suggesting that a rapidly reversible enhancement of glucocorticoid action may occur in the late G1 phase when histones are hyperacetylated. This rapidly reversible process appears to be distinct from the more slowly reversible cell cycle population effects.

Butyrates↗
PubMed1996

Effects of the ratio of ruminal propionate to butyrate on milk yield and blood metabolites in dairy cows.

Four Ayrshire cows (mean = 56 DIM) were used in a 4 x 4 Latin square design to study the effects of the ratio of propionate to butyrate in the rumen on milk yield, milk composition, and blood metabolites. The cows were fed a basal diet (16.2% CP, 43.4% NDF) consisting of 50% grass silage, 6% grass hay, and 44% concentrate (percentage of DM). The diet supplied 44 Mcal/d of metabolizable energy and was supplemented with isoenergetic infusions of VFA (4.5 Mcal/d). Propionate (900 g/d) was replaced gradually with 33, 67, and 100% of butyrate on an energy basis. Replacement of propionate with butyrate in the infusate decreased propionate and increased butyrate concentrations in ruminal fluid and in blood plasma. Yields of milk and lactose decreased, and yield of milk fat increased, as butyrate increased. Milk fat content increased, and lactose content decreased, as butyrate increased. Increased ruminal supply of butyrate decreased plasma glucose concentration and increased blood ketone body concentration. When only butyrate was infused (750 g/d), either liver metabolism was changed or tissue mobilization was increased, as indicated by the increased production of long-chain milk fatty acids and increased plasma concentrations of acetate, Gly, and branched-chain AA. An increase in ruminal butyrate supply at the expense of propionate adversely affected milk yield and the repartitioning of nutrients between milk components. At a high percentage, increased butyrate might also adversely affect the overall metabolism of the cow.

3-Hydroxybutyric Acid↗
PubMed1990

Characterization of sublines of HL-60 human leukemia cells resistant to induction of differentiation by butyric acid.

HL-60 human leukemia cells undergo terminal differentiation when cultured with butyric acid. To produce cells resistant to the maturation-inducing effects of butyric acid, two strategies were followed. First, HL-60 cells were mutagenized and cultured in soft agar with inducing concentrations of butyric acid. Four clones were isolated resistant to a wide variety of differentiation inducers, including butyric acid. Second, HL-60 cells were cultured in gradually increasing concentrations of butyric acid until a normal growth rate was achieved in medium containing greater than 1 mM butyric acid. These cells retained their ability to be induced to mature to neutrophils with dimethylsulfoxide, retinoic acid, and actinomycin D; and to monocyte/macrophage like cells with tetradecanoylphorbol acetate and 1,25-(OH)2 vitamin D3. However, they no longer underwent terminal differentiation when butyric acid was added in increasing concentration, even when cytotoxic concentrations were used. The mutagenized clones cells appeared permanently butyrate resistant, but the selected clones reverted to the wild-type state when grown in the absence of butyric acid. The selected cells continued to express myeloperoxidase; the mutagenized lines did not. Thus, by using two different protocols, HL-60 cells resistant to the cytotoxic and maturation-inducing effects of butyric acid can be produced that have varied phenotypic characteristics.

Butyrates↗
PubMed1985

Biosynthesis of heparin. Effects of n-butyrate on cultured mast cells.

Murine mastocytoma cells were incubated in vitro with inorganic [35S]sulfate, in the absence or presence of 2.5 mM n-butyrate, and labeled heparin was isolated. The polysaccharide produced in the presence of butyrate showed a lower charge density on anion exchange chromatography than did the control material and a 3-fold increased proportion (54 versus 17% for the control) of components with high affinity for antithrombin. Structural analysis of heparin labeled with [3H] glucosamine in the presence of butyrate showed that approximately 35% of the glucosamine units were N-acetylated, as compared to approximately 10% in the control material; the nonacetylated glucosamine residues were N-sulfated. The presence of butyrate thus leads to an inhibition of the N-deacetylation/N-sulfation process in heparin biosynthesis, along with an augmented formation of molecules with high affinity for antithrombin. Preincubation of the mastocytoma cells with butyrate was required for manifestation of either effect; when the preincubation period was reduced from 24 to 10 h the effects of butyrate were no longer observed. Assays for microsomal N-acetylheparosan deacetylase activity failed to show any significant inhibition of the enzyme at butyrate concentrations well above those found to affect heparin biosynthesis in intact mastocytoma cells. Moreover, a polysaccharide formed on incubating mastocytoma microsomal fraction with UDP-[3H]glucuronic acid, UDP-N-acetylglucosamine, and 3'-phosphoadenylylsulfate in the presence of 5 mM butyrate showed the same N-acetyl/N-sulfate ratio as did the corresponding control polysaccharide, produced in the absence of butyrate. These findings suggest that the effect of butyrate on heparin biosynthesis depends on the integrity of the cell.

Amidohydrolases↗