Suppression of cytoplasmic protein uptake by lysosomes as the mechanism of protein regain in livers of starved-refed mice.

The suppression of proteolysis that normally accompanies cytoplasmic growth was investigated in livers of mice that had lost approximately 40% of their protein content during 48 h of starvation. The deficit was fully restored after 24 h of refeeding, and the net regain was linear between 12 and 24 h. Rates of protein breakdown were determined from (a) differences between synthesis and the net change in total liver protein, and (b) rates of valine release during 15-min in situ perfusions in the presence of cycloheximide. With appropriate correction for the turnover of a short lived pool, both procedures gave the same results; rates at 12 and 24 h of refeeding were decreased 90% over values in fed controls, an effect which accounted for 93% of protein regrowth. Measurements of degradable, intralysosomal protein revealed that sequestration of cytoplasmic protein by lysosomes was correspondingly decreased. Because the ratio of intracellular proteolysis to internalized protein was the same during refeeding as in earlier experiments where autophagy was the dominant process, the uptake of cytoplasmic proteins by lysosomes appears to be an obligatory step in proteolysis at all levels of regulation. The 20-fold range in rates of degradation exhibited by the mouse hepatocyte thus provides this cell with an unusual capability for regulating its protein content against relatively small changes in protein synthesis.