Arachidonate and medium-chain fatty acids inhibit transcription of the acetyl-CoA carboxylase gene in hepatocytes in culture

Abstract

Transcription of acetyl-CoA carboxylase in avian liver is low during starvation or after consumption of a low-carbohydrate, high-fat diet and high during consumption of a high-carbohydrate, low-fat diet. The role of fatty acids or metabolites derived from fatty acids in the nutritional control of acetyl-CoA carboxylase transcription was investigated by determining the effects of long- and medium-chain fatty acids on acetyl-CoA carboxylase expression in primary cultures of chick embryo hepatocytes. Palmitate, oleate, and arachidonate caused a decrease in acetyl-CoA carboxylase activity in hepatocytes incubated with triiodothyronine (T3). The inhibition of acetyl-CoA carboxylase activity caused by arachidonate was accompanied by a similar decrease in transcription of the acetyl-CoA carboxylase gene. In contrast, neither palmitate nor oleate were effective in modulating acetyl-CoA carboxylase transcription. These results are consistent with arachidonate or a metabolite derived therefrom mediating the effects of diets containing high levels of n-6 polyunsaturated fatty acids on acetyl-CoA carboxylase transcription in liver. Hexanoate and octanoate also inhibited acetyl-CoA carboxylase activity in the presence of T3. The magnitude of the hexanoate- or octanoate-induced decrease in acetyl-CoA carboxylase activity was greater than that observed for long-chain fatty acids. Hexanoate and octanoate inhibited acetyl-CoA carboxylase activity at a transcriptional step, and did so within 2 h of addition of fatty acid. Addition of carnitine partially reversed the inhibitory effects of octanoate on acetyl-CoA carboxylase expression, suggesting that a metabolite of octanoate is involved in mediating this response. 2-Bromooctanoate was a more potent inhibitor of acetyl-CoA carboxylase expression than octanoate or hexanoate. We postulate that a metabolite of hexanoate and octanoate, possibly a six or eight carbon acyl-CoA, plays a role in the nutritional regulation of acetyl-CoA carboxylase transcription.