RT Journal Article SR Electronic T1 Short-Chain Fatty Acid Metabolism, Apoptosis, and Apc-initiated Tumorigenesis in the Mouse Gastrointestinal Mucosa JF Cancer Research JO Cancer Res FD American Association for Cancer Research SP 6005 OP 6009 VO 59 IS 23 A1 Augenlicht, Leonard H. A1 Anthony, Gillian M. A1 Church, Trudi L. A1 Edelmann, Winfried A1 Kucherlapati, Raju A1 Yang, Kan A1 Lipkin, Martin A1 Heerdt, Barbara G. YR 1999 UL http://cancerres.aacrjournals.org/content/59/23/6005.abstract AB Short-chain fatty acids (SCFAs) are physiological regulators of growth and differentiation in the gastrointestinal tract, and we have previously shown that apoptosis induced in colonic cell lines by these compounds is dependent on their metabolism by B-oxidation in the mitochondria (B. G. Heerdt et al., J. Biol. Chem., 266: 19120–19126, 1991; Cancer Res., 54: 3288–3293, 1994). Because tumors initiated by an inherited Apc mutation have been reported to be linked to decreases in apoptosis in the flat mucosa of the gastrointestinal tract, the aims were to determine whether elimination of efficient metabolism of SCFAs affected apoptosis in the gastrointestinal mucosa of the mouse, and whether this altered tumorigenesis initiated by an inherited Apc mutation. We, therefore, generated mice that have a chain-terminating mutation in the Apc gene and that were either wild-type for SCFA metabolism, or deficient, due to homozygous deletion of the gene (Scad) that encodes the enzyme short-chain acyl dehydrogenase, which catalyzes the first step in SCFA B-oxidation. Scad+/+ mice maintained on a wheat bran-fiber-supplemented diet gained significantly more weight than mice maintained on AIN76A, but this was eliminated by the Scad mutation, demonstrating that uptake and metabolism of SCFAs in the gastrointestinal tract can be a significant energy source. As predicted, on either AIN76A or wheat bran diet, the Scad mutation almost completely eliminated apoptosis in the flat mucosa of the proximal colon and reduced apoptosis by 50% in the distal colon compared with littermates that were wild-type for Scad. The mutation also reduced apoptosis by approximately 50% in the duodenum in AIN76A-fed mice. These reductions in apoptosis had no effect on incidence, frequency, or site specificity of tumors initiated by the Apc mutation. Therefore, the metabolism of SCFAs by the gastrointestinal mucosa plays a role in modulating apoptosis, but a general decrease in apoptosis in the mucosa of the gastrointestinal tract is not linked to gastrointestinal tumorigenesis initiated by an inherited Apc mutation. ©1999 American Association for Cancer Research.