Inhibition of lipid synthesis by beta beta'-tetramethyl-substituted, C14-C22, alpha, omega-dicarboxylic acids in the rat in vivo

beta beta'-Methyl-substituted alpha, omega-dicarboxylic acids (MEDICA) of C14-C18 chain length were found to inhibit liver lipid synthesis in the rat in vivo. Maximum inhibition was observed with MEDICA 16 amounting to a 50% decrease in fatty acid and cholesterol biosynthesis in the presence of 0.07 and 0.015% (w/w) of the drug in the diet, respectively. Inhibition of lipid biosynthesis by MEDICA 16 involved a reduction in cytosolic acetyl-CoA content, while the carbon flux from glucose to glycogen, protein, and carbon dioxide remained unaffected. Inhibition of lipogenesis by MEDICA 16 resulted in a 50% decrease in liver and carcass (but not brain) neutral lipid ester content at 0.25% (w/w) of the drug in the diet, as well as in a dose-dependent hypotriglyceridemic effect, with an up to 3-fold reduction in serum triacylglycerols. Inhibition of cholesterogenesis by MEDICA 16 resulted in a hypocholesterolemic effect, with 60 and 45% reductions in (very low density + low density lipoprotein) cholesterol and high density lipoprotein cholesterol, respectively.