Control of cell protein catabolism in rat liver. Effects of starvation and administration of cycloheximide

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Abstract
The loss of liver protein occurring in rats starved for 24 h was largely prevented by the administration of repeated doses of cycloheximide, an inhibitor of protein synthesis. Similar effects were produced on tubulin, a fixed liver protein. Starvation accelerated, whereas cycloheximide markedly lowered, the rate of protein radioactivity decay after labeling with [3H]valine or [14C]bicarbonate, indicating that changes in catabolic rates played an important role in the above regulations of liver protein mass. The total activity of several lysosomal hydrolases showed little change in livers of starved rats, but a marked progressive decline developed after the administration of cycloheximide, particularly in the activities of cathepsins B, D and L as well as acid RNase. There was no evidence that these changes might be due to endogenous inhibitors (at least for cathepsin B activity, which fell to < 30% of the control values) or enzyme leakage into the bloodstream; rather, plasma .beta.-galactosidase and .beta.-N-acetylglucosaminidase activities fell progressively during the cycloheximide treatment. Endogenous proteolytic rates, measured in vitro by incubating subcellular preparations from livers prelabeled in vivo with [3H]valine, were markedly decreased in cycloheximide-treated animals. The osmotic fragility of hepatic lysosomes, appreciably enhanced in starved animals, after cycloheximide treatment was even lower than in fed controls. In starved animals the loss of liver protein is probably mostly accounted for by increased breakdown, due, in part at least, to enhanced autophagocytosis. Cycloheximide largely counteracted these effects of starvation, altering the liver from being poised in a proteolytic direction to a protein-sparing condition. Besides suppression of the autophagic processes, a decrease in the lysosomal proteolytic enzyme system may also play a role in this regulation. Circumstantial evidence is presented for the existence of co-ordinating mechanisms between protein synthesis and degradation.