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PubMed2007

Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier.

Production of short-chain fatty acids (SCFA) in the intestinal lumen may play an important role in the maintenance of the intestinal barrier. However, overproduction/accumulation of SCFA in the bowel may be toxic to the intestinal mucosa and has been hypothesized to play a role in the pathogenesis of neonatal necrotizing enterocolitis (NEC). By using a Caco-2 cell monolayer model of intestinal barrier, we report here that the effect of butyrate on the intestinal barrier is paradoxical. Butyrate at a low concentration (2 mM) promotes intestinal barrier function as measured by a significant increase in transepithelial electrical resistance (TER) and a significant decrease in inulin permeability. Butyrate at a high concentration (8 mM) reduces TER and increases inulin permeability significantly. Butyrate induces apoptosis and reduces the number of viable Caco-2 cells in a dose-dependent manner. Intestinal barrier function impairment induced by high concentrations of butyrate is most likely related to butyrate-induced cytotoxicity due to apoptosis. We conclude that the effect of butyrate on the intestinal barrier is paradoxical; i.e. whereas low concentrations of butyrate may be beneficial in promoting intestinal barrier function, excessive butyrate may induce severe intestinal epithelial cell apoptosis and disrupt intestinal barrier.

Apoptosis↗
PubMed1999

Butyrate switches the pattern of chemokine secretion by intestinal epithelial cells through histone acetylation.

BACKGROUND: Butyrate, a fermentation product of intestinal bacteria, modifies chromatin structure through histone acetylation, thereby altering gene transcription. IL-8 and MCP-1 are chemokines, expressed by intestinal epithelial cells, which attract neutrophils and monocytes, respectively. We hypothesized that butyrate may alter IL-8 and MCP-1 expression by intestinal epithelial cells through histone acetylation. MATERIALS AND METHODS: IL-8 and MCP-1 expression was measured by ELISA and RNA transfer blots. Acetylated histones were separated on acetic acid-urea-triton gels. Butyrate was compared to Trichostatin-A, a specific inhibitor of histone deacetylase and to other short chain fatty acids. RESULTS: Caco-2 cells constitutively secreted MCP-1 but not IL-8. Butyrate reversibly decreased MCP-1 secretion. In contrast, butyrate increased IL-8 production. The effects of butyrate and Trichostatin-A were greater when cells were stimulated with IL-1beta. Butyrate and Trichostatin-A both increased histone acetylation. Trichostatin-A and other short chain fatty acids altered chemokine secretion according to their effect on histone acetylation. CONCLUSIONS: Butyrate reversibly switches chemokine secretion by epithelial cells through histone acetylation. We speculate that butyrate carries information from resident bacteria to epithelial cells. Epithelial cells transduce this signal through histone acetylation, modulating the secretion of chemokines.

Acetylation↗
PubMedDate not supplied

Inhibition of proliferation, invasion and adhesion of liver cancer cells by 5-azacytidine and butyrate.

BACKGROUND: The prognosis for liver cancer is poor with current chemotherapeutic agents, for the most part, ineffective. We have recently shown that 5-azacytidine (5-azaC) and butyrate stimulate apoptosis in two human liver cancer cell lines (HepG2 and Hep3B). The purpose of our present study was to determine the effects of these agents on proliferation, invasion and adhesion of liver cancer cells, and to assess potential cellular mechanisms for these effects. MATERIALS AND METHODS: HepG2 and Hep3B cells were treated with either 5-azaC (8 microM), sodium butyrate (35 mM), 5-azaC + butyrate or vehicle (control); proliferation, cellular invasion and adherence were determined. Western blots were performed to assess expression levels of p21waf1, p27kip1 and p53. RESULTS: Treatment with 5-azaC alone inhibited invasion of Hep3B cells whereas butyrate alone inhibited invasion of HepG2 cells; the combination of 5-azaC + butyrate completely suppressed the invasion of both cell lines. Moreover, cellular adhesion and proliferation were inhibited in both cell lines by combination treatment. Levels of the Cdk inhibitor p21waf1 were increased in HepG2 cells after 5-azaC and in both cell lines after butyrate treatment; levels of p27kip1 were increased in both cell lines after either 5-azaC or butyrate treatment. CONCLUSIONS: Our results demonstrate that the combination of 5-azaC and butyrate effectively blocks proliferation, invasion and cellular adhesion of both HepG2 and Hep3B cells. Increases in the expression of the cell cycle inhibitory proteins, p21waf1 and p27kip1 suggest that these effects may be mediated through the induction of these inhibitory proteins. Agents such as 5-azaC and butyrate that target the cell cycle pathway may prove clinically useful in the adjuvant treatment of liver cancers.

Azacitidine↗
PubMedDate not supplied

Apoptosis induced by the sodium butyrate in human gastric cancer TMK-1 cells.

The effects of sodium butyrate on cell proliferation, gene expression, and apoptosis were investigated. Upon exposure to sodium butyrate the cells exhibited marked morphological changes, reduced cell proliferation and most cells died through apoptosis within 48 hours. In the presence of dexamethasone, however, the sodium butyrate-triggered apoptosis was markedly reduced. Studies using the glucocorticoid receptor antagonist RU486 indicated that the protective effect of dexamethasone was mediated through glucocorticoid receptor. Sodium butyrate markedly induced the c-jun proteins level, whereas the c-Myc protein was down-regulated rapidly. c-Jun protein may play an important role in the action of sodium butyrate since its induction preceded the onset of DNA fragmentation. In addition, preincubation of the cells with dexamethasone markedly delayed the induction of c-jun levels by sodium butyrate. Analysis of the expression of bel-2-related genes indicated that the Bcl-xS protein level was increased in the presence of sodium butyrate and the up-regulation of Bcl-xS by sodium butyrate was also blocked by dexamethasone. Taken together, these results indicate that c-myc, c-jun and Bcl-xS proteins may be involved in the mechanism of sodium butyrate-triggered apoptosis in these cells.

Apoptosis↗
PubMed2000

Ligand-independent activation of the androgen receptor by the differentiation agent butyrate in human prostate cancer cells.

Androgens are potent differentiation agents that regulate prostate-specific antigen (PSA) gene expression via the androgen receptor (AR) that binds to androgen response elements (AREs) on the PSA gene to initiate transcription. However, in the absence of androgens, PSA gene expression can become elevated. This suggests that either the AR can be activated in the absence of androgen to elevate PSA gene expression through AREs on the PSA gene or that another transcription factor acting on the PSA promoter is stimulated. We have previously shown in vivo that butyrate, a differentiation agent that causes cell cycle arrest, increases serum PSA levels in castrated animals. Therefore, to determine the mechanism of butyrate induction of PSA, we used the LNCaP human prostate cancer cell line. Northern analyses and transfection experiments using a PSA reporter plasmid demonstrated induction of PSA gene expression by butyrate in LNCaP cells. Application of the antiandrogen bicalutamide blocked the induction of PSA mRNA by butyrate, suggesting a mechanism dependent on the AR. Consistent with this conclusion, electromobility shift assays showed increased AR-ARE complex formation with nuclear extracts from butyrate-treated cells. In addition, other reporter gene constructs that contain AREs were also induced by butyrate. Western blot analysis showed an increase in nuclear levels of AR protein in cells exposed to butyrate, whereas whole cell levels remained unchanged, suggesting that butyrate causes nuclear translocation of the AR. Thus, the differentiation agent butyrate causes ligand-independent activation of the AR to increase expression of the differentiation marker PSA in human prostate cancer cells.

Androgen Antagonists↗
PubMedDate not supplied

Synergistic cytotoxicity of artemisinin and sodium butyrate on human cancer cells.

BACKGROUND: Butyric acid is a short chain fatty acid produced by large bowel bacterial flora. It serves as an antiinflammatory agent and nutrient for normal colon cells. Butyric acid has also been shown to induce apoptosis in colon and many other cancer cells. Artemisinin is a compound extracted from the wormwood Artemisia annua L. It has been shown to selectively kill cancer cells in vitro and to be effective in treating animal and human cancer. We and others have found that the artemisinin analog, dihydroartemisinin (DHA), kills cancer cells by apoptosis. In the present study, the efficacy of a combined treatment of DHA and butyric acid at low doses in killing cancer cells was investigated. MATERIALS AND METHODS: Molt-4 cells (a human lymphoblastoid leukemia cell line) and freshly isolated human lymphocytes, cultured in complete RPMI-1640 medium, were first incubated with 12 microM of human holotransferrin at 37 degrees C in a humid atmosphere of 5% CO2 for one hour to enhance the iron concentration in the cells. Cells from each cell type were then divided into 20 flasks. These flasks were grouped into four sets of five cultures each. Zero, 5, 10 or 20 microM of DHA was added, respectively, to these sets and the cells were incubated at 37 degrees C for one hour. Zero, 1, 5, 10, or 20 mM of sodium butyrate was then added to the five cultures of each set, respectively. Thus, the treatments involved a combination of 4 doses of DHA and 5 doses of sodium butyrate. The cells were counted immediately before the addition of DHA, and at 24 and 48 hours after the addition of sodium butyrate. RESULTS: DHA alone at the 24-hour time-point and 20 microM concentration significantly reduced the number of Molt-4 cells in the culture by approximately 40% (p < 0.001, compared to non-treated control), whereas it did not significantly affect the number of normal human lymphocytes. Similarly, 1 mM sodium butyrate alone at 24 hours reduced the number of Molt-4 cells by approximately 32% (p < 0.001, compared to non-treated control), without significantly affecting normal human lymphocytes. The combination of 20 microM DHA and 1 mM sodium butyrate killed all Molt-4 cells at the 24-hour time-point and did not significantly affect lymphocytes. CONCLUSION: DHA in combination with butyric acid acts synergistically at low doses. The combination may provide a less toxic, inexpensive and effective cancer chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Butyrate production from oligofructose fermentation by the human faecal flora: what is the contribution of extracellular acetate and lactate?

Butyrate is an important substrate for maintenance of colonic health and oligofructose fermentation by human faecal bacteria can increase butyrate production in vitro. However, oligofructose appears to be fermented by mainly acetate and lactate-producing bacteria rather than butyrate-producing bacteria. Isotope labelling studies using [U-(13)C(6)]glucose were used to show that (13)C(2) and (13)C(4) were the major labelled butyrate species produced from glucose fermentation, via [(13)C(2)]acetate-acetyl CoA as intermediate. Bacterial interconversion reactions were quantified and acetate conversion to butyrate and lactate conversion to acetate, propionate and butyrate were observed. Addition of oligofructose to faecal batch cultures significantly increased butyrate production. Of the newly synthesised butyrate from oligofructose fermentation, 80 % was derived from interconversion of extracellular acetate and lactate, with acetate being quantitatively more significant. Carbohydrates, such as oligofructose, have prebiotic properties. In addition, oligofructose selectively stimulates the bacterial conversion of acetate and lactate to butyrate. Carbohydrates with similar properties represent a refinement of the prebiotic definition, termed butyrogenic prebiotics, because of their additional functionality.

Acetates↗
PubMed2006

Apoptosis of U937 human leukemic cells by sodium butyrate is associated with inhibition of telomerase activity.

Sodium butyrate as a histone deacetylase inhibitor is known to exhibit anti-cancer effects via the differentiation and apoptosis of various carcinoma cells. However, the mechanism by which sodium butyrate induces apoptosis and the involvement of telomerase activity during apoptosis is not completely understood. To investigate the underlying pathways, sodium butyrate's potential to induce apoptosis in human leukemic U937 cells and its effects on telomerase activity were investigated. Exposure of U937 cells to sodium butyrate resulted in growth inhibition and induction of apoptosis in a dose-dependent manner as measured by hemocytometer counts, fluorescence microscopy, agarose gel electrophoresis and flow cytometry analysis. The increase in apoptosis was associated with the up-regulation in pro-apoptotic Bax expression, and down-regulation of anti-apoptotic Bcl-2 and Bcl-XL. Sodium butyrate treatment also inhibited the levels of cIAP family members and induced the activation of caspase-3. Furthermore, sodium butyrate markedly inhibited the activity of telomerase and the expression of human telomerase reverse transcriptase (hTERT), a main determinant of the telomerase enzymatic activity, was progressively down-regulated by sodium butyrate. Taken together, it is suggested that sodium butyrate can be a promising chemopreventive agent for leukemic cells and changes in Bcl-2 family expressions, as well as telomerase activity may, play critical roles in sodium butyrate-induced apoptosis in U937 cells.

Apoptosis↗
PubMed1979

Induction of cholera toxin receptors in cultured cells by butyric acid.

Exposure of HeLa cells to sodium butyrate caused an increase in choleragen (cholera toxin) receptors as measured by increased binding of 125I-choleragen to the intact cells. The process was dependent on time and butyrate concentration; maximal increases (over 40-fold) were observed at 48 h and 5 mM sodium butyrate. Other short chain fatty acids were less effective in elevating choleragen receptors in the order: butyrate greater than pentanoate greater than hexanoate greater than propionate. Acetate and isobutyrate had no effect. The increase in toxin receptors caused by butyrate was reversible and occurred in serum-free medium. The affinity of choleragen for control and butyrate-treated HeLa cells appeared to be similar. Butyrate also induced an elevation in choleragen receptors in rat C6 glial and Friend erythroleukemic cells but not in a butyrate-resistant HeLa mutant. The increase observed in Friend cells paralleled the increase in ganglioside GM1 (galactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide), the reported choleragen receptor. Although no GM1 could be detected in untreated Hela cells, small amounts were found in cells exposed to butyrate.

Animals↗
PubMed1981

Manifold effects of sodium butyrate on nuclear function. Selective and reversible inhibition of phosphorylation of histones H1 and H2A and impaired methylation of lysine and arginine residues in nuclear protein fractions.

In addition to its known effect in suppressing the deacetylation of the nucleosomal core histones, sodium butyrate in the concentration range 0.5 to 15 mM causes a selective inhibition of [32P]phosphate incorporation into histones H1 and H2A of cultured HeLa S3 cells. No commensurate general inhibition of phosphorylation is seen in the non-histone nuclear proteins of butyrate-treated cells, but phosphorylation patterns are altered and 32P-uptake may be stimulated, as well as inhibited, depending upon the protein fraction analyzed. The degree of inhibition of histone phosphorylation in intact cells increases progressively as the butyrate concentration is raised from 0.5 to 15 mM. The effect is time-dependent and fully reversible. Butyrate has no effect on the kinetics of phosphate release from previously phosphorylated histones of cultured cells, nor does it significantly alter the rate of dephosphorylation of 32P-labeled histone H1 by endogenous phosphatases in vitro. Despite the suppression of [32P]phosphate incorporation into histones H1 and H2A of butyrate-treated cells, Na-butyrate does not inhibit the in vitro activities of either type I or type II cyclic AMP-dependent protein kinases, or the cAMP-independent H1 kinase associated with cell cycle progression. This suggests that the butyrate effect on histone phosphorylation in vivo is indirect and may involve an alteration in substrate accessibility or a modulation of systems affecting kinase activities. The poly(ADP)-ribosylation of HeLa histones is not inhibited by 5 mM Na-butyrate. Cells exposed to butyrate show an impaired methylation of lysine and arginine residues in their histones and nuclear hnRNP particles, respectively.

Arginine↗
PubMed1985

Isolation of a Butyrate-Utilizing Bacterium in Coculture with Methanobacterium thermoautotrophicum from a Thermophilic Digester.

Sludge from a thermophilic, 55 degrees C digester produced methane without a lag period when enriched with butyrate. The sludge was found by most-probable-number enumeration to have ca. 5 x 10 butyrate-utilizing bacteria per ml. A thermophilic butyrate-utilizing bacterium was isolated in coculture with Methanobacterium thermoautotrophicum. This bacterium was a gram-negative, slightly curved rod, occurred singly, was nonmotile, and did not appear to produce spores. When this coculture was incubated with Methanospirillum hungatei at 37 degrees C, the quantity of methane produced was less than 5% of the methane produced when the coculture was incubated at 55 degrees C, the routine incubation temperature. The coculture required clarified digester fluid. The addition of yeast extract to medium containing 5% clarified digester fluid stimulated methane production when a Methanosarcina sp. was present. Hydrogen in the gas phase prevented butyrate utilization. However, when the hydrogen was removed, butyrate utilization began. Penicillin G and d-cycloserine caused the complete inhibition of butyrate utilization by the coculture. The ability of various ecosystems to convert butyrate to methane was studied. Marine sediments enriched with butyrate required a 2-week incubation period before methanogenesis began. Hypersaline sediments did not produce methane after 3 months when enriched with butyrate.

Journal Article↗
PubMed1998

Modulation of galectin-1 content in human head and neck squamous carcinoma cells by sodium butyrate.

Galectin-1 and galectin-3 are beta-galactoside-binding proteins thought to be important for cellular interactions, growth regulation and differentiation. Alterations in cellular content of galectins have been associated with differentiation, transformation and malignant progression. We examined the modulation of galectin-1 and galectin-3 expression in head and neck squamous cell carcinoma (HNSCC) cell lines by treatment with sodium butyrate, a known differentiation-modulating agent, and identified potential mechanisms of butyrate regulation of galectin-1 levels in one of the cell lines. Sodium butyrate effected an increase in galectin-1 protein concentration in 5 of 8 cell lines. One cell line, MDA-886LN, showed a marked time- and dose-dependent increase from barely detectable amounts with butyrate treatment. Concurrently with increased galectin-1 expression, butyrate treatment promoted morphologic changes, induced growth inhibition and inhibited soft agar colony formation in MDA-886LN cells. Butyrate-treated MDA-886LN cells demonstrated increased galectin-1 mRNA content, suggesting a role for butyrate in transcriptional regulation of galectin-1 expression. Treatment with other inhibitors of histone deacetylase also induced an increase in galectin-1 expression. Together, our results indicate that butyrate treatment can modulate galectin-1 content in MDA-886LN HNSCC cells as well as induce morphologic changes and growth inhibition. This action may involve a combination of transcriptional regulation and inhibition of histone deacetylation.

Animals↗
PubMed1996

n-Butyrate induces plasminogen activator inhibitor type 1 messenger RNA in cultured Hep G2 cells.

n-Butyrate, a short-chain aliphatic carboxylic acid with pleiotropic actions, is present at high concentrations in the portal circulation and thus may play an important role in the regulation of specific gene expression in the mammalian liver. We report here that n-butyrate can increase substantially the level of plasminogen activator inhibitor type 1 (PAI-1) messenger RNA (mRNA) in Hep G2 cells, up to eightfold above control cultures. Maximal effects occurred at a concentration of 3 mmol/L n-butyrate and with a treatment period of 8 to 12 hours. Increases in PAI-1 mRNA were accompanied by modest increases (twofold) in the encoded protein as assessed by specific enzyme-linked immunosorbent assay and by [35S]methionine incorporation into immunoprecipitable PAI-1 in the culture medium. Nuclear run-on studies showed that the rate of transcription of the PAI-1 gene did not appear altered by treatment with 3 mmol/L n-butyrate for 6 hours. The increases in steady-state PAI-1 mRNA caused by exposure to n-butyrate can be blocked by cycloheximide. Enhanced stability of mature PAI-1 transcript could not be demonstrated in Hep G2 cells treated with the carboxylic acid. We have reported previously that n-butyrate can reduce the level of beta-galactoside alpha 2,6-sialyltransferase expression in Hep G2 cells. That effect was attenuated with inhibitors of protein and RNA synthesis and was mediated at the post-transcriptional level. Thus, n-butyrate can influence the expression of multiple genes in this hepatoblastoma cell through its actions on events that appear to be posttranscriptional. These observations may be relevant to the normal physiology of the mammalian liver because of the high concentrations of n-butyrate and related compounds to which the organ is ordinarily exposed.

Butyrates↗
PubMed1995

Butyrate and TGF-beta downregulate Na,K-ATPase expression in cultured proximal tubule cells.

Attempts were made to examine the effect of growth inhibitors on regulation of Na,K-ATPase in primary cultures of renal proximal tubule cells. We observed that both TGF-beta and butyrate induced dose dependent decrease of Na,K-ATPase activity. The time course studies showed that the effect of TGF-beta preceded the effect of butyrate on inhibition of Na,K-ATPase activity. Both butyrate- and TGF-beta-induced inhibition of this enzyme were in general mediated by transcriptional decreases of alpha and beta mRNA and therefore also protein abundance. Like its effect on Na,K-ATPase activity, TGF-beta compared to butyrate induced much earlier decline in Na,K-ATPase alpha and beta mRNA and protein abundance. Butyrate did not affect gene expression of TGF-beta and anti-TGF-beta antibody had no effect on butyrate-induced inhibition of DNA synthesis. Obviously, both butyrate and TGF-beta can inhibit the expression of Na,K-ATPase alpha and beta mRNA, but TGF-beta does not mediate butyrate's effect.

Animals↗
PubMed1984

Glucose requirement for induction by sodium butyrate of the glycoprotein hormone alpha subunit in HeLa cells.

Butyric acid produces multiple effects on mammalian cells in culture, including alterations in morphology, depression of growth rate, increased histone acetylation, and modified production of various proteins and enzymes. The latter effect is exemplified by the induction in HeLa cells of the glycoprotein hormone alpha subunit by millimolar concentrations of the fatty acid. This report demonstrates that increased subunit accumulation in response to sodium butyrate is strikingly dependent on the presence of glucose (or mannose) in the growth medium. In contrast, basal levels of subunit synthesis are only marginally affected when the culture medium is supplemented with one of a variety of hexoses. An increase in the accumulation of HeLa alpha does not occur in medium containing pyruvate as the energy source, and sustained induction requires the simultaneous and continued presence of both glucose and butyrate. The effects of butyrate on HeLa cell morphology and subunit induction can be separated, since the latter is glucose-dependent while the former is not. Failure of butyrate to induce alpha in medium containing pyruvate does not result from restricted subunit secretion, since the levels of intracellular alpha are not increased disproportionately relative to those in the medium. The hexoses which support induction of HeLa alpha (glucose greater than or equal to mannose greater than galactose greater than fructose) are identical to those which have been shown previously to stimulate the glucosylation of lipid-linked oligosaccharides and enhance the synthesis of certain glycoproteins. Labeling of various glycosylation intermediates with [3H]mannose indicates that in glucose medium there is a decrease in the level of radioactivity associated with both dolicholpyrophosphoryl oligosaccharide and cellular glycoproteins and a concomitant increase in the fraction of label recovered in secreted glycoproteins. Butyrate also causes a decrease in [3H]mannose-labeled cellular glycoproteins and an increase in tritiated extracellular glycoproteins, particularly in glucose medium. Likewise, glucose stimulates the incorporation of [3H]glucosamine into immunoprecipitable alpha subunit relative to the bulk of HeLa-secreted glycoproteins, and this is further enhanced by butyrate. However, as demonstrated by lectin chromatography of conditioned media, a nonglycosylated subunit does not accumulate in pyruvate medium, either in the absence or presence of butyrate.(ABSTRACT TRUNCATED AT 400 WORDS)

Butyrates↗
PubMed1986

Butyrate effects on normal and adapted hepatoma cells: morphological response and implications for vectoral cholesterol transport.

The cell line 4IC6, adapted for growth in 6 mM sodium butyrate from Hepatoma Tissue Culture cells [R. Chalkley, and A. Shires (1985) J. Biol. Chem. 260, 7698-7704], exhibits a fourfold increase in histone acetate turnover. The 4IC6 cells were about 25 times more resistant to butyrate relative to the parental cell line as measured by cloning efficiency. This line also maintains a flatter and more extended morphology when growing in the presence of 6 mM sodium butyrate relative to the parental line. Both cell lines maintain similar intracellular butyrate levels and incorporate [1-14C]butyrate into lipids to similar extents when incubated in medium containing high levels of the fatty acid. These results show that 4IC6 cells have not attained butyrate resistance through acquiring the ability to metabolize butyrate more efficiently or in a significantly different manner when compared with the parental cell line. The membrane lipid composition was nearly identical between the two cell types. Thus the different morphologies exhibited by each cell line were not a consequence of altered membrane lipid composition. The resistant line, 4IC6, maintains about 10-fold higher cholesterol ester levels and half the level of triglycerides found in the parental line. The butyrate-resistant cells also synthesize cholesterol at about a 1.8-fold higher rate than do the parental cells. This difference in de novo synthesis is reflected by a difference of a similar factor in the amount of radioactive cholesterol the two cell lines accumulate over 12 generations. These results are discussed with respect to models for equilibration of serum lipoprotein-derived and newly synthesized cholesterol.

Acetates↗
PubMed1988

The effect of sodium butyrate on tyrosine aminotransferase induction in primary cultures of normal adult rat hepatocytes.

Treatment of primary cultures of adult rat hepatocytes with 5 mM butyrate inhibited the spontaneous decrease in basal activity and mRNA levels of tyrosine aminotransferase (TAT) that occurred during culture (Staecker et al., submitted). We report here that butyrate treatment of primary cultures of rat hepatocytes initially inhibited the induction of TAT. This inhibition was followed by a period of accelerated TAT induction. TAT induction in butyrate-treated primary cultures of adult rat hepatocytes occurred only after metabolism of butyrate by the cultured hepatocytes. The accelerated induction of TAT in hepatocyte cultures treated with sodium butyrate was reflected by increased TAT activity and mRNA levels. Cultured hepatocytes rapidly metabolized butyrate, but the addition of more butyrate into cultures after its initial metabolism resulted in a rapid reduction in TAT activity. These findings indicate that butyrate treatment can affect the expression of TAT in primary hepatocyte cultures in both a positive (increased basal TAT expression) and a negative (inhibition of the induced expression of TAT) manner.

Acetylation↗
PubMed1994

Butyrate stimulates the secretion of apolipoprotein B-100-containing lipoproteins from HepG2 cells by inhibiting the intracellular degradation.

We have shown previously that sodium butyrate induces a 2-fold increase in the secretion of apo B-100 by HepG2 cells. The apo B-100 mRNA level was not changed in butyrate-treated cells, indicating regulation at the translational or co- or posttranslational level (Biochem. J. (1991) 278, 557-564). In this paper, the mechanism by which butyrate increases apo B-100 secretion was further investigated. Pulse-chase analysis showed that in control incubations only 18 +/- 4% of the total amount of labelled apo B-100, present intracellularly after a 10 min pulse period, was secreted after a 90 min chase period, indicating that the major part of newly synthesized apo B-100 is degraded intracellularly. After addition of butyrate the secreted amount increased to 32 +/- 6% of the total synthesized amount. Treatment of HepG2 cells with butyrate resulted in an enhanced intracellular concentration of triacylglycerols (+30%), with no or only a marginal effect on the cellular content of cholesterol and cholesteryl esters. Secretion of triacylglycerols (+90%) and cholesteryl esters (+78%), but not of cholesterol, was increased to the same extent as apo B-100 secretion (+102%). The total mass of triacylglycerols, i.e., the sum of triacylglycerols present intracellularly and secreted by HepG2 cells, was significantly increased upon incubation with butyrate (+32%), whereas the total mass of cholesteryl esters was not affected. Butyrate did not affect the buoyant density of apo B-100-containing lipoproteins secreted by HepG2 cells. These results suggest that an increased availability of triacylglycerols, formed after the addition of butyrate regulates the amount of apo B-100 degraded intracellularly and consequently apo B-100 secretion.

Albumins↗