The effects of the short-chain aliphatic carboxylic acid, n-butyrate, on glycosaminoglycan (GAG) accumulation were studied in cultured human skin fibroblasts. Normal fibroblast cultures were grown to confluence, shifted to a medium without or with n-butyrate for 24 h, labeled with either VHlacetate or V3Hjglucosamine and analyzed for IHIGAG and V3Hjhyaluronate accumulation. Accumulation was stimulated at low concentrations (0.1-1 mM) by up to 27%. Higher concentrations of n-butyrate (> 1 mM) inhibited V3HIGAG by up to 70-90%. This effect was maximal at 10 mM and half-maximal at 3 mM. Propionate had similar effects but was less potent. Parallel studies conducted in colonic fibroblasts revealed that n-butyrate could markedly inhibit I3HIGAG accumulation in that cell type as well. These effects were rapid, occurring within 3 h of treatment, and were reversible. Chondroitin sulfate accumulation was unaffected by the compound. A pulse-chase study failed to demonstrate any effect on 13HIGAG degradation.