Effect of dichloroacetic acid on rat hepatic messenger RNA activity profiles

We have previously suggested that the ability of glucose to induce rat hepatic lipogenic enzymes is mediated by the mitochondrial oxidation of pyruvate. In part, this hypothesis is supported by the finding that an activator of pyruvate dehydrogenase, dichloroacetic acid (DCA), is capable of inducing malic enzyme in hepatocyte cultures. In order to further test this hypothesis, we compared the mRNA responses induced by carbohydrate feeding in vivo and by glucose administration to hepatocytes in culture with those mRNA responses induced in DCA both in vivo and in culture. DCA administration to rats resulted in a significant increase in liver:body weight ratio. It was, in addition, a potent inducer of malic enzyme. Hepatic mRNA activity profiles were examined by two-dimensional gel electrophoretic analysis of in vitro translation products. Six of the seven mRNAs altered by carbohydrate feeding were similarly altered by DCA feeding in vivo. In cultured hepatocytes 10 mmol/L DCA significantly increased four of six glucose-induced mRNAs. The mRNA for malic enzyme was among those mRNA sequences induced both in vivo and in culture. Increasing glucose concentrations in the culture medium resulted in an expected rise in pyruvate levels, whereas DCA caused a significant decrease in the concentration of this intermediate. It is likely, therefore, that augmentation of the flux of pyruvate through pyruvate dehydrogenase rather than alterations in pyruvate levels per se, is a proximal event leading to the induction of multiple mRNAs. The marked overlap in mRNA response to both carbohydrate and DCA indicates that the signal regulating the content of the carbohydrate responsive mRNAs is derived from mitochondrial pyruvate oxidation.