Lysosomal pathways in hepatic protein degradation: regulatory role of amino acids.
Cytoplasmic protein in hepatocytes is continuously internalized and degraded by two lysosomal processes, 1) overt or macroautophagy, and 2) microautophagy, the latter involving dense bodies. The first is acutely regulated by amino acids, insulin, and glucagon; the second is also alterable, but responses are slower and probably adaptive in nature, as suggested in starvation-refeeding. Internalized protein in lysosomes was independently assessed from 1) lysosomal volumes and hepatocyte protein concentration and 2) its degradation products in liver homogenates; quantitative agreement was obtained between the two determinations. Agreement was equally close when the results were used to predict rates of hepatic proteolysis over the full range, assuming that k for all sequestered protein is equal to the turnover of macroautophagic vacuoles (0.087 min-1). These findings strongly indicate that internalization is an obligatory step in both phases of protein degradation. Acute proteolytic responses to amino acids were studied in rat livers perfused in the single-pass mode. Twelve amino acids exhibited no suppressive activity at the upper physiological limit of plasma amino acid concentrations (4 X normal), whereas seven were fully effective as a group. Of these, leucine was the most inhibitory at 4 X, but was inactive as 1 X. Deletion of the other regulatory amino acids from normal plasma mixtures, however, accelerated proteolysis strikingly as did omission of glutamine, glutamate, alanine, and glycine. Of the latter, only glutamine was directly inhibitory although its effectiveness was low. Restraint to protein degradation at normal plasma concentrations appears to be complex and to involve specific amino acid regulators as well as glucogenic amino acids in ways not yet understood.
D000596:Amino Acids / Q000502:physiology*; D000818:Animals; D001343:Autophagy; D005973:Glutamine / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D007930:Leucine / Q000502:physiology; D008099:Liver / Q000378:metabolism* / Q000648:ultrastructure; D008247:Lysosomes / Q000502:physiology* / Q000648:ultrastructure; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D014617:Vacuoles / Q000502:physiology; D014633:Valine / Q000378:metabolism
D000596:Amino Acids; D011506:Proteins; D005973:Glutamine; D007930:Leucine; D014633:Valine