Inhibition of lipid synthesis by beta beta'-tetramethyl-substituted, C14-C22, alpha, omega-dicarboxylic acids in cultured rat hepatocytes.

beta beta'-Methyl-substituted, C14-C18, alpha, omega-dicarboxylic acids (MEDICA 14-18) were found to inhibit fatty acids and cholesterol synthesis in cultured rat hepatocytes. Maximum inhibition was observed with MEDICA 16, amounting to a 50% decrease in 3H2O and acetate incorporation into fatty acids and cholesterol in the presence of 0.08 mM of the drug added to the culture medium. Inhibition of lipogenesis was not accompanied by inhibition of palmitate or glycerol esterification into neutral lipids and phospholipids. The respective capacities of MEDICA homologues of varying acyl chain length as inhibitors of fatty acid and cholesterol synthesis in cultured rat hepatocytes and in vivo (Bar-Tana, J., Rose-Kahn, G., and Srebnik, M. (1985) J. Biol. Chem. 260, 8404-8410) correlated well with their respective inhibitory effect on liver ATP-citrate lyase. Thus, MEDICA 16 inhibited liver ATP-citrate lyase competitively to citrate with a Ki of 16 microM as compared to a Km of 0.8 mM for the citrate substrate.