Multiphasic control of hepatic protein degradation by regulatory amino acids. General features and hormonal modulation.
Previous studies with livers from fed rats perfused in the single-pass mode have shown that regulatory amino acids (Leu, Tyr, Gln, Pro, Met, His, and Trp) as a group as well as leucine alone inhibit deprivation-induced protein degradation optimally at 0.5 and 4 times (X) normal plasma amino acid concentrations. However, they lose inhibitory effectiveness almost completely within a narrow zone centered at normal (1 X) levels (Pösö, A. R., Wert, J. J., Jr., and Mortimore, G.E. (1982) J. Biol. Chem. 257, 12114-12120; Pösö, A. R., and Mortimore, G. E. (1984) Proc. Natl. Acad. Sci. U. S. A. 81, 4270-4274). We now report similar effects for tyrosine and glutamine and suggest that this multiphasic dose response is a general feature of the regulatory group. Insulin (2.4 micrograms h-1) selectively modulated the response by abolishing the zonal loss, whereas glucagon (10 micrograms h-1) blocked the initial inhibition (0.5 X); proteolytic suppression was restored at 4 X normal plasma levels. Although the zonal loss of inhibition at 1 X was associated with a near maximal increase in the volume density of macroautophagy, the vacuoles differed from those induced by stringent amino acid deprivation in containing 4.5-fold more smooth than rough endoplasmic reticulum and thus represented a separate population. Surprisingly, the leucine analog, L-alpha-hydroxyisocaproate, elicited multiphasic responses identical to those of L-leucine, including inhibition at 0.1 mM (equivalent to 0.5 X Leu). Inasmuch as alpha-ketoisocaproate is not effective at this concentration, the initial suppression of protein degradation could be mediated from a site that recognizes structural features common to leucine and its hydroxyl analog.
Mortimore
G E
GE
Department of Physiology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033.
Pösö
A R
AR
Kadowaki
M
M
Wert
J J
JJ
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D002208:Caproates / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew
D000596:Amino Acids; D002208:Caproates; D007328:Insulin; D011506:Proteins; C034527:isocaproic acid; D005934:Glucagon