Studies on the mechanism of carbohydrate repression in rat liver

Abstract In earlier published studies we have shown that the amino acid catabolizing enzymes, threonine dehydrase and ornithine transaminase, can be rapidly induced in the livers of protein depleted rats force-fed casein hydrolysate or injected with glucagon. This induction, which is inhibited by the administration of gamma irradiation, actinomycin, puromycin, or fluoroorotic acid, is also inhibited by the forced feeding of glucose or fructose. The kinetic picture of the inhibition by carbohydrate feeding appears to resemble that produced by puromycin administration rather than by actinomycin or fluoroorotic acid administration, suggesting that the repressive effect of carbohydrate is exerted at the stage of protein synthesis involving peptide formation. The feeding of carbohydrates is accompanied by the rapid accumulation of large quantities of glycogen in the liver, and when glucagon is injected into rats receiving dietary glucose the resultant enzyme induction is accompanied by a decrease in liver glycogen concentration. During the course of these studies we have evolved the working hypothesis that the metabolic control phenomena which we have observed (induction and repression) arise through the interaction of enzyme forming systems with intracellular lipoprotein membranes such as the endoplasmic reticulum. Agents which alter the configuration of these membranes and/or their association with the enzyme forming systems (polysomes) might be expected correspondingly to affect induction and repression. For example, when glycogen is deposited in the liver cell after feeding carbohydrate, it appears to become associated with the endoplasmic reticulum. Numerous workers have shown that this endoplasmic reticulum is morphologically quite different (tubular network, no ribosomes attached to membranes) from that not associated with glycogen (lamellar network, ribosomes attached to membranes) and it is possible that such morphological differences may be accompanied by differences in metabolic properties. In the further exploration of this hypothesis we have tested the effects of a variety of hormones on the induction and repression of certain amino acid catabolizing enzymes (serine dehydrase, ornithine transaminase, and tyrosine transaminase), the rationale being that hormones may exert their metabolic action through an effect on membrane structure. We observed that in protein depleted rats which have been pretreated with cortisone (5 mg/day for 3 days) glucose repression of enzyme induction is significantly less than that in rats not given cortisone. We also found, however, that induction by casein hydrolysate without glucose is substantially less in rats treated with cortisone as compared to those not receiving cortisone. The administration of cortisone alone does not produce significant enzyme induction under the conditions of these experiments. These results suggest that cortisone exerts a “protective” effect on the induction process, permitting induction to occur in the face of carbohydrate, but not itself causing induction. Similar effects are produced by triamcinolone, but deoxycorticosterone has no effect on the induction or repression phenomena. Experiments were also conducted to study the possibility that carbohydrate repression may in fact be a consequence of increased insulin production stimulated by the carbohydrate feeding. No suppression of induction occurs when rats receiving casein hydrolysate are injected with insulin at dosages just below lethality.