Effects of aliphatic alcohols and fatty acids on the metabolism of acetate by rat liver slices.

Abstract

The effects of the addition of normal aliphatic alcohols and fatty acids on the metabolism of acetate by rat liver slices have been investigated, with particular reference to the formation, from acetate-1-C14, of C14O2and radioactive lipids, proteins, and fatty acids. Whereas the addition of unlabelled acetate causes a fall in the rate of formation of C14O2, the decrease, at low concentrations, is less than that calculated for isotopic dilution. This is probably due to the fact that with an increased concentration of acetate there is an increased rate of acetate oxidation. However, the addition of ethanol causes a larger fall in the rate of formation of C14O2than would be expected if the alcohol were converted to acetate. This points to some inhibition by ethanol of acetate oxidation, a conclusion borne out by the inhibitory effects of n-alcohols on total CO2formation (in the absence and in the presence of added acetate) by rat liver slices. The fact, however, that the inhibitory effect of ethanol reaches a maximum at 5 mmolar and is constant to 50 mmolar points against a major inhibition due to ethanol per se. The results would be consistent with the conclusion that ethanol, at low concentrations, is more quickly converted into acetyl-CoA than acetate itself and that its speed of conversion into acetyl-CoA reaches a maximum at about 5 mmolar with rat liver slices. n-Propanol is much more inhibitory than ethanol but its effect is quantitatively identical with that of an equivalent quantity of propionate. Propionate and n-propanol are presumably rapidly converted to propionyl-CoA (or methyl malonyl-CoA), which is the effective inhibitor of acetate oxidation by its competition with acetyl-CoA. Propanol also shows direct inhibitory effects on acetate oxidation in rat liver slices. n-Butanol, n-pentanol, and n-hexanol have inhibitory effects identical with those of equivalent concentrations of corresponding fatty acids. These facts point to the oxidation, in rat liver, of aliphatic alcohols and fatty acids to propionyl-CoA or acetyl-CoA which inhibit C14O2formation from acetate-1-C14by competition or isotopic dilution. Alternations of inhibition occur between the odd- and even-numbered carbon alcohols and fatty acids which may be explained by the formation of mixtures of acetyl-CoA and the highly inhibitory propionyl-CoA from the long-chain alcohols and acids. Tribromoethanol is less inhibitory than propanol at equivalent concentrations though it is an effective inhibitor of acetate oxidation. Allyl alcohol is a much more potent inhibitor. Ethanol inhibits incorporation of radioactivity of acetate-1-C14into fatty acids in rat liver, the inhibition being approximately equal to, or possibly less than, that due to an equivalent quantity of acetate. This may be explained on the basis of isotopic dilution, by acetyl-CoA derived from the alcohol, with radioactive acetyl-CoA undergoing synthesis to radioactive fatty acids. Thus ethanol, at the concentrations investigated, by taking part in fatty acid synthesis, inhibits acetate conversion to fatty acids. Glucose shows the largest effect in stimulating fatty acid synthesis in the liver from acetate, fructose is less effective, and sorbitol shows no effect. The aliphatic alcohols inhibit incorporation of radioactivity from acetate-1-C14into liver lipids and proteins, propanol and pentanol showing the largest effects. There is an alternation between odd- and even-numbered aliphatic chains. The disappearance, or utilization, of acetate by rat liver slices is inhibited by the aliphatic alcohols, alternations between the odd- and even-numbered chains again being observable. The results are explained as being partly due to isotopic dilution and competition by acetyl-CoA and propionyl-CoA, and partly due to suppressions of acetate metabolism by the alcohols.