HEPATIC FATTY-ACID SYNTHASE GENE-TRANSCRIPTION IS INDUCED BY A DIETARY COPPER DEFICIENCY

A dietary copper (Cu) deficiency is associated with a twofold increase in hepatic fatty acid biosynthesis. We hypothesized that the inductio n of hepatic lipogenesis associated with a dietary Cu deficiency refle cted an enhanced expression of genes encoding lipogenic enzymes, i.e., fatty acid synthase (FAS). Male weanling rats were pair-meal fed for 42 days a high-sucrose diet that was Cu deficient (CuD; 0.7 mu g Cu/g) or Cu adequate (CuA; 5.0 mu g Cu/g). The CuD diet increased FAS enzym atic activity twofold (P < 0.05). This rise in enzymatic activity was accompanied by a threefold increase in FAS mRNA and a 2.5-fold increas e in FAS gene transcription (P < 0.05). Neither the mRNA abundance nor the rate of gene transcription for phosphoenolpyruvate carboxykinase or beta-actin was affected by the CuD diet. The induction of FAS gene transcription was associated with a 65-85% increase in hepatic reduced glutathione (GSH; P < 0.05). When hepatic GSH synthesis was suppresse d by treating CuD rats with L-buthionine sulfoximine, the induction of FAS expression was completely prevented. Similarly, feeding N-acetylc ysteine to CuA rats increased hepatic GSH levels 2.5-fold, and this wa s accompanied by a significant induction in FAS expression. These data indicate that the increase in hepatic lipogenesis associated with a C u deficiency reflects an induction in hepatic lipogenic gene transcrip tion (i.e., FAS) and that the rate of gene transcription may be depend ent on hepatic thiol redox.