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ABSTRACT: Butyrate, a short-chain fatty acid produced by the colonic bacterial fermentation is able to induce cell growth inhibition and differentiation in colon cancer cells at least partially through its capacity to inhibit histone deacetylases. Since butyrate is expected to impact cellular metabolic pathways in colon cancer cells, we hypothesize that it could exert its antiproliferative properties by altering cellular metabolism. We show that although Caco2 colon cancer cells oxidized both butyrate and glucose into CO(2) , they displayed a higher oxidation rate with butyrate as substrate than with glucose. Furthermore, butyrate pretreatment led to an increase cell capacity to oxidize butyrate and a decreased capacity to oxidize glucose, suggesting that colon cancer cells, which are initially highly glycolytic, can switch to a butyrate utilizing phenotype, and preferentially oxidize butyrate instead of glucose as energy source to produce acetyl coA. Butyrate pretreated cells displayed a modulation of glutamine metabolism characterized by an increased incorporation of carbons derived from glutamine into lipids and a reduced lactate production. The butyrate-stimulated glutamine utilization is linked to pyruvate dehydrogenase complex since dichloroacetate reverses this effect. Furthermore, butyrate positively regulates gene expression of pyruvate dehydrogenase kinases and this effect involves a hyperacetylation of histones at PDK4 gene promoter level. Our data suggest that butyrate exerts two distinct effects to ensure the regulation of glutamine metabolism: it provides acetyl coA needed for fatty acid synthesis, and it also plays a role in the control of the expression of genes involved in glucose utilization leading to the inactivation of PDC.
International Journal of Cancer 06/2011; 128(11):2591-601. · 5.44 Impact Factor
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ABSTRACT: The polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) reduces proliferation of several cell types, including colon tumor cells, and regulates gene expression in a cell- and gene-selective manner. In hepatocytes, the fatty acid synthase (FAS) gene is down-regulated by DHA whereas the carnitine palmitoyltransferase-1 (CPT-1) gene is up-regulated. In adipocytes but not in hepatocytes, the expression of the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) gene is stimulated by unsaturated FA, including DHA. We monitored the expression of the FAS, CPT-1 and PEPCK-C genes in rat and human colon and in colonic tumors from humans. The ratio of PEPCK-C to FAS transcripts was in favor of PEPCK-C in human and rat colon, whereas the opposite occurred in Caco2 tumoral cells. FAS gene expression declined from proliferative to differentiated Caco2 cells, while in contrast the expression of PEPCK-C and CPT-1 genes increased. DHA strongly induced expression of the PEPCK-C and CPT-1 genes, in correlation with decreased cell growth, while, as expected, it reduced FAS mRNA. We assessed the relative expression of PEPCK-C, CPT-1 and FAS genes in fragments of colonic tumors and adjacent non-tumoral tissue from a series of 10 patients. PEPCK-C and CPT-1 mRNAs are more abundant in non-tumoral tissues than in the tumoral counterpart, whereas the opposite occurred for the FAS gene. Therefore, the PEPCK-C gene can be defined as a new negative marker for colonic tumors and a target for the anti-tumorigenic action of omega-3 PUFAs.
Biochimie 12/2010; 92(12):1772-7. · 3.02 Impact Factor
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ABSTRACT: Pyruvate dehydrogenase complex (PDC) serves as the metabolic switch between glucose and fatty acid utilization. PDC activity is inhibited by PDC kinase (PDK). PDC shares the same substrate, i.e., pyruvate, as glyceroneogenesis, a pathway controlling fatty acid release from white adipose tissue (WAT). Thiazolidinediones activate glyceroneogenesis. We studied the regulation by rosiglitazone of PDK2 and PDK4 isoforms and tested the hypothesis that glyceroneogenesis could be controlled by PDK.
Rosiglitazone was administered to Zucker fa/fa rats, and then PDK4 and PDK2 mRNAs were examined in subcutaneous, periepididymal, and retroperitoneal WAT, liver, and muscle by real-time RT-PCR. Cultured WAT explants from humans and rats and 3T3-F442A adipocytes were rosiglitazone-treated before analyses of PDK2 and PDK4 mRNA and protein. Small interfering RNA (siRNA) was transfected by electroporation. Glyceroneogenesis was determined using [1-(14)C]pyruvate incorporation into lipids.
Rosiglitazone increased PDK4 mRNA in all WAT depots but not in liver and muscle. PDK2 transcript was not affected. This isoform selectivity was also found in ex vivo-treated explants. In 3T3-F442A adipocytes, Pdk4 expression was strongly and selectively induced by rosiglitazone in a direct and transcriptional manner, with a concentration required for half-maximal effect at 1 nmol/l. The use of dichloroacetic acid or leelamine, two PDK inhibitors, or a specific PDK4 siRNA demonstrated that PDK4 participated in glyceroneogenesis, therefore altering nonesterified fatty acid release in both basal and rosiglitazone-activated conditions.
These data show that PDK4 upregulation in adipocytes participates in the hypolipidemic effect of thiazolidinediones through modulation of glyceroneogenesis.
Diabetes 09/2008; 57(9):2272-9. · 8.29 Impact Factor
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ABSTRACT: A substantial body of evidence supports the conclusion that chronic inflammation is a causative factor in a variety of cancers. Inflammatory mediators include metabolites of arachidonic acid, cytokines, chemokines, and free radicals. These mediators increase cell proliferation, mutagenesis, oncogene activation, with ultimately the loss of cell growth control. Among the nutritional factors that can influence inflammation and cancerogenesis, fatty acids are clearly the most directly involved. Indeed, omega-3 and omega-6 polyunsaturated fatty acids exert opposite effects on inflammation and potentially on tumor formation. The present review analyses in a non-exhaustive manner some of the mechanisms that have been proposed to explain how omega-6 can be detrimental while omega-3 have beneficial effects.
OCL - Oleagineux Corps Gras Lipides 09/2006; 13(5-OCL VOL. 13 N° 5 SEPTEMBRE-OCTOBRE 2006):331-336.
