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Genes responsive to sodium butyrate in colonic epithelial cells

ABSTRACT: We performed global scale microarray analysis to identify detailed mechanisms by which sodium butyrate (SB) induce cell growth arrest and differentiation of colonic epithelial cells by using an Affymetrix GeneChip system. Colonic epithelial MCE301 cells used in this study were derived from transgenic mice harboring a tsSV40 large T-antigen. Arrested cell growth and a differentiated phenotype accompanying elevations of alkaline phosphatase activity and histone acetylation were observed in the cells treated with 2 mM SB. Of the 22,690 probe sets analyzed, approximately 2,000 genes were down- and up-regulated by a factor of 2.0 or greater in the cells treated with SB. Keywords: sodium butyrate, gene expression, colonic epithelial cell

ORGANISM(S): Mus musculus

PROVIDER: GSE4410 | GEO | 2006/03/10

SECONDARY ACCESSION(S): PRJNA94641

REPOSITORIES: GEO

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Project description:Machado-Joseph disease (MJD) is a fatal neurodegenerative disease caused by expansion of the trinucleotide repeat region within the ATXN3/MJD gene. Mutation of ATXN3 causes formation of neurotoxic ataxin-3 protein aggregates, neurodegeneration and motor deficits. Here we investigated the therapeutic potential and mechanistic activity of sodium butyrate (SB), the sodium salt of butyric acid, a metabolite naturally produced by gut microbiota, on cultured SH-SY5Y cells and transgenic zebrafish expressing human ataxin-3 containing 84 glutamine (Q) residues to model MJD. MJD SH-SY5Y cells were found to contain ataxin-3 oligomeric species and protein aggregates. Treatment with SB increased activity of the autophagy protein quality control pathway in the MJD cells, decreased presence of ataxin-3 aggregates and presence of ataxin-3 oligomers in an autophagy-dependent manner. Treatment with SB was also beneficial in vivo, improving swimming performance, increasing autophagy activity and decreasing presence of insoluble ataxin-3 protein species in the transgenic MJD zebrafish. Co-treating the MJD zebrafish with SB and chloroquine, an autophagy inhibitor, prevented the beneficial effects of SB on the zebrafish swimming, suggesting that the improved swimming performance was autophagy-dependent. To identify mechanism of the induction of autophagy by SB, we performed proteomic analysis of protein lysates from the SB treated and untreated MJD SH-SY5Y cells. We found that SB treatment had increased activity of Protein Kinase A and AMPK signaling. Immunoblot analysis confirmed that SB treatment had increased levels of acetylated FOXO1 protein. Further, co-treatment with an inhibitor of FOXO1 transcriptional activity (AS1842856) prevented the increase in autophagosome formation (LC3II/I) usually produced by SB treatment. Together our findings indicate that treatment with SB can increase activity of the autophagy pathway through a FOXO1-dependent process and that this has beneficial effects in vitro and in vivo. We propose that treatment with sodium butyrate warrants further investigation for the treatment of neurodegenerative diseases underpinned by proteinopathy mechanisms, including MJD.

Project description:Butyrate has a central function in the regulation of energy metabolism as a metabolite of bacterial fermentation. However, information on the direct impact of butyrate on peripheral organs or tissues is very limited, especially for muscle and adipose tissues. Therefore, this study evaluated the effects of intravenous sodium butyrate (SB) administration on the transcriptome of muscle and adipose tissue of pigs. Twelve crossbred barrows (Duroc × Landrace × Large White, 60 days of age) were fitted with a medical polyethylene cannula via internal jugular vein and were daily infused with 10 ml SB (200 mmol/l) or the same volume of physiological saline. After a 7-day experimental period, all pigs were slaughtered, and the longissimus dorsi muscle and dorsal subcutaneous adipose tissue were collected for holistic transcriptomic analysis. In muscle tissue, the expression of 12 oxidative phosphorylation related genes and seven glycolysis related genes were downregulated. Furthermore, the mRNA expression of fatty acid synthase (FASN) and stearyl coenzyme A desaturase (SCD) were significantly upregulated by SB treatment. This indicates a decrease in oxidative phosphorylation and glucose catabolism, and an increase in fat synthesis. In adipose tissue, the expressions of seven oxidative phosphorylation-related genes were downregulated, while nine glucose metabolism related genes were upregulated. Moreover, the mRNA expressions of FASN and peroxisome proliferator-activated receptor gamma (PPARγ) were upregulated, while fatty acid binding protein 3 (FABP3) and acyl-CoA synthetase long-chain family member 1 (ACSL1) were downregulated in the SB group. This indicates a decrease in oxidative phosphorylation and an increase in glucose metabolism and fat synthesis. The results suggest that short-term intravenous SB infusion can modulate muscle and adipose tissue metabolism at the transcriptional level by decreasing both oxidative phosphorylation and fat synthesis. In addition, intravenous SB decreases the glucose catabolism in muscle tissue and increases the glucose catabolism in adipose tissue. This suggests that systemic butyrate may display discriminative metabolic regulation in different tissues of barrows.

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Genes responsive to sodium butyrate in colonic epithelial cells

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