Dietary
polyunsaturated fatty acids (PUFA) of the (n-6) and (n-3) families uniquely suppress the expression of lipogenic genes while concomitantly inducing the expression of genes encoding
proteins of
fatty acid oxidation. Although considerable progress has been made toward understanding the nuclear events affected by PUFA, the intracellular mediator responsible for the regulation of hepatic lipogenic gene expression remains unclear. On the basis of earlier
fatty acid composition studies, we hypothesized that the Delta-6 desaturase pathway was essential for the production of the
fatty acid regulator of gene expression. To address this hypothesis, male BALB/c mice (n = 8/group) were fed for 5 d a high
glucose,
fat-free diet (FF) or the FF plus 50 g/kg 18:2(n-6) with and without eicosa-5, 8,11,14-tetraynoic
acid (
ETYA) (200 mg/kg diet), a putative inhibitor of the Delta-6 desaturase pathway.
ETYA had no effect on food intake or
weight gain, but it completely prevented 18:2(n-6) from suppressing the hepatic abundance of
fatty acid synthase mRNA.
ETYA ingestion was associated with a decrease in the hepatic content of 20:4(n-6) and an increase in the amount of 18:2(n-6). The
fatty acid composition changes elicited by
ETYA were accompanied by a decrease in the enzymatic activity of Delta-6 desaturase. Interestingly, the hepatic abundance of Delta-6 desaturase
mRNA was actually induced by
ETYA one- to twofold. When the product of Delta-6 desaturase, i.e., 18:3(n-6), was added to the
ETYA plus 18:2(n-6) diet, the hepatic content of 20:4(n-6) was normalized. In addition, 18:3(n-6) consumption reduced the level of hepatic Delta-6 desaturase
mRNA by 50% and completely prevented the increase in
fatty acid synthase mRNA that was associated with
ETYA ingestion. Apparently, Delta-6 desaturation is an essential step for the PUFA regulation of the
fatty acid synthase gene transcription. Finally, the suppression of Delta-6 desaturase by PUFA and its induction by
ETYA suggest that the Delta-6 desaturase gene may be regulated by two different
lipid-dependent mechanisms.