Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Regulation of Protein Metabolism in Liver

Glenn E. Mortimore, Motoni Kadowaki

10.1002/cphy.cp070217

Source: Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism

Originally published: 2001

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Turnover of Cellular Protein and RNA
1.1 Determination of General Protein Turnover
1.2 Classes of General Protein Turnover
1.3 Cytoplasmic RNA Turnover
2 Autophagy
2.1 Macroautophagy
2.2 Microautophagy
2.3 A Unified Mechanism of Macro‐ and Microautophagic Proteolysis
3 Regulation of Autophagy
3.1 Control of Macroautophagy by Amino Acids
3.2 Hormonal Control of Cellular Protein Turnover
3.3 Control of Macro‐ and Microautophagy during Starvation and Refeeding
4 Overview
Figure 1. Figure 1.

Release of free [14C]valine from short‐ and long‐lived proteins in the perfused mouse liver. Livers from fed and 48 h starved‐refed mice were perfused in the single‐pass mode and pulse‐labeled for 10 min with [14C]valine and a normal mixture of plasma amino acids. Perfusion then was switched to a medium containing 15 mM valine; after a 10 min washout, the remaining medium (with 15 mM valine) was recirculated for 110 min. Open circles, total free label release; open triangles, short‐lived release, calculated as the difference between total and the linear, long‐lived component. Inset, degradation of long‐lived or resident proteins in livers of fed mice, previously radiolabeled with valine in vivo (compare with long‐lived component in pulse‐labeled fed control mice). From Hutson and Mortimore 52, with permission of the publisher.
Figure 2. Figure 2.

Scheme showing major lysosomal/autophagic vacuolar (AV) compartments in the rat hepatocyte. Nascent AVs are left of the broken line; mature forms are to the right. Nascent initial macro‐AVs (AVi) are formed from rough endoplasmic reticulum 33; nascent micro‐AVs are single‐walled vesicles, probably from smooth endoplasmic reticulum 89. They produce type A (autophagic) lysosomes after fusing with a type R (residual body) or another type A lysosome. The AVis mature to digestive vacuoles after acidification and subsequent fusion with type R lysosomes 34. End products of macro‐AVs include a few type A but mostly type R lysosomes. The point where endosomes join the lysosomal/vacuolar pathway is not fully settled and is not shown (see text for discussion). Electron microscopic illustrations: for AVi, see Schworer et al. 127 and Mortimore and Kadowaki 87; for type A and type R secondary lysosomes, see Mortimore et al. 89 and Surmacz et al. 136.
Figure 3. Figure 3.

Time course of macroautophagic vacuole (AV) formation and regression. A: Livers from normal fed rats were perfused in parallel without added amino acids and, at intervals, fixed for electron microscopy. Volume densities of initial (AVi), digestive (AVd), and total AVs were taken from Schworer et al. 127. B: Livers were perfused in parallel for 20 min without amino acids; at time zero, 10 x plasma amino acids were added. Volume densities were determined as in A. Inset: Semilogarithmic plot of the regression of total AV volume.

[From Schworer et al. 127 with permission.]
Figure 4. Figure 4.

Correlations between proteolysis, aggregate volumes of initial (AVi) and digestive (AVd) autophagic vacuoles, and the shift of β‐hexosaminidase from lysosomes to AVi during deprivation‐induced macroautophagy in perfused livers of fed rats. A: Relationship between accelerated long‐lived proteolysis (filled circles), and the above shift of β‐hexosaminidase (open circles), at various levels of plasma amino acids. The shift, which was determined in lysosomal‐vacuolar fractions separated in colloidal silica gradients 135, 136, is a measure of lysosomal‐AVi fusion 123. B: Correlation of AVi (open triangles), AVd (filled triangles), and the β‐hexosaminidase shift versus rates of deprivation‐induced proteolysis.

[From Surmacz et al. 134 with permission.]
Figure 5. Figure 5.

Relationship between long‐lived proteolysis and pools of intralysosomal degradable protein in rat liver over the full range of protein turnover. The quantity of valine residues in the protein pools per gram tissue from livers in various accelerated (open triangles), and basal (filled triangles) states of protein degradation was correlated with corresponding rates of proteolysis monitored from valine release. The above regression equation was y = ‐0.0002 + 0.0882x (r = 0.999), based on data from three studies 53, 89, 96 corrected for an intralysosomal pH of 4.5 93.
Figure 6. Figure 6.

Correlation between hepatic RNA degradation and lysosomal pools of degradable RNA. Livers from nonstarved rats, previously labeled with [14]orotic acid, were perfused with plasma amino acids over the full range of regulated RNA turnover (compare with Fig. 5). Breakdown of RNA in liver and in liver lysosomal particles was determined from [14]cytidine release as detailed by Heydrick et al. 48. Broken line displays total homogenate RNA breakdown (lysosome + cytosol); solid line gives total minus cytosolic breakdown rates. NML refers to homogenate fractions containing nuclei, mitochondria, and lysosomes 48.

[From Heydrick et al. 48 with permission.]
Figure 7. Figure 7.

Relationship between basal protein turnover and volume densities of type A and type R lysosomes during short‐term starvation in rat liver. Livers from fed and 48 h starved rats were perfused with 10 X plasma amino acids for the measurement of basal long‐lived proteolysis and stereological analysis of secondary lysosomes 89. Under‐ and over‐estimation of type A and type R elements, respectively, were corrected by multiplying the observed type A volumes 89 by 1.285, which equalized its slope to that of the total (see discussion in text); type R was then determined by subtracting type A from the total. Type A lysosomes were also assumed to be underestimated by ≈2% because of random sections through electron‐lucent zones. This correction increased the total ≈1% but did not affect type R. The type A volumes shown include closed invagination forms 89. IBW, initial body weight.
Figure 8. Figure 8.

Proteolytic dose‐response modes (H and L) to leucine in isolated hepatocytes from ad libitum‐fed rats. Responses to leucine and alanine were measured in 13 experiments, each on a different day. Responses to leucine (1X Leu + 1X Ala) on different days spontaneously fell into one of two randomly alternating modes, termed H and L.

[From Venerando et al. 143 with permission.]
Figure 9. Figure 9.

Proteolytic dose responses to regulatory amino acids. Livers from normal fed rats were perfused in the single‐pass mode with various regulatory amino acids (Reg AA) at fractions/multiples of their concentrations in a reference 1X plasma mixture. The 1X mixture was composed of the following (μM): Leu, 204; Gln, 716; Tyr, 98; Pro, 437; Met, 60; His, 92; Trp, 93 94, 143.

[From Mortimore et al. 94 with permission.
Figure 10. Figure 10.

Proteolytic dose responses to leucine, glutamine, and leucine + glutamine. Experiments were carried out as in Figure 9 except that livers were obtained from synchronously fed, 24 h starved rats. Molar values for leucine and glutamine on the abscissa (bottom) correspond to fractions/multiples of their concentrations in the reference plasma mixture (top) given in Figure 9. Values are means ± SE of 3 to 33 experiments, normalized to 100 g of initial body weight. AA, amino acid.

[From Miotto et al. 81 with permission.].
Figure 11. Figure 11.

Proteolytic dose responses to the standard complete amino acid (AA) mixture and to leucine + alanine. V represents proteolytic inhibition, expressed as nmol valine·min‐1 per liver (100 g of initial body weight); S denotes fractions/multiples of amino acids in the medium. In this plot, Vmax is shown as the V intercept. The apparent Km values are also relative (rel.) in that they are based on fractions/multiples of the molar values in the standard plasma mixture. A: Responses of livers from normal fed rats to the complete amino acid mixture. B: Responses of livers from synchronously fed, 24 h starved rats to the same mixture and to leucine + alanine.

[From Miotto et al. 81 with permission.]
Figure 12. Figure 12.

Nonreducing polyacrylamide gel electrophoresis showing a photolabeled plasma membrane protein of Mr ≈340,000 that had entered a 7.5% to 20% gradient gel. Labeling was strongly protected by 20 mM leucine in parallel runs. Fresh rat hepatocytes were photolyzed with (125I‐azidosalicylic acid) Leu7‐multiple antigen peptide ± 20 mM leucine, and the plasma membrane fraction was extracted with 2% sodium dodecyl sulfate for electrophoresis. No photolabeling was obtained with similar photoprobes constructed with valine or isoleucine.

[From Mortimore et al. 98 with permission.]
Figure 13. Figure 13.

Effects of 10‐9 M insulin on proteolytic dose responses to regulatory (Reg. AA) and complete plasma amino acid mixtures. In other respects, the experiments were the same as those in Figure 9.

[From Mortimore et al. 94 with permission.].
Figure 14. Figure 14.

Effect of 8 × 10‐9 M glucagon on the proteolytic dose‐response curve to regulatory amino acids (Reg. AA). The conditions otherwise were the same as those in Figure 9.

[From Mortimore et al. 94 with permission.]
Figure 15. Figure 15.

Alterations in the content of liver protein (upper panel), and in rates of protein synthesis and degradation (lower panel) during starvation and refeeding in the mouse. Rates of resident protein synthesis were determined as previously detailed 53; observed degradation rates were calculated by difference from the net changes in protein content in the upper panel. Observed degradation rates agreed closely with predicted rates based on stereologically determined volumes of digestive autophagic vacuoles and microautophagic vacuoles, the turnover of autophagic vacuoles, and estimates of cytoplasmic protein concentration using procedures and control stereological data from Blouin et al. 15.

[From Mortimore et al. 86 with permission.]


Figure 1.

Release of free [14C]valine from short‐ and long‐lived proteins in the perfused mouse liver. Livers from fed and 48 h starved‐refed mice were perfused in the single‐pass mode and pulse‐labeled for 10 min with [14C]valine and a normal mixture of plasma amino acids. Perfusion then was switched to a medium containing 15 mM valine; after a 10 min washout, the remaining medium (with 15 mM valine) was recirculated for 110 min. Open circles, total free label release; open triangles, short‐lived release, calculated as the difference between total and the linear, long‐lived component. Inset, degradation of long‐lived or resident proteins in livers of fed mice, previously radiolabeled with valine in vivo (compare with long‐lived component in pulse‐labeled fed control mice). From Hutson and Mortimore 52, with permission of the publisher.



Figure 2.

Scheme showing major lysosomal/autophagic vacuolar (AV) compartments in the rat hepatocyte. Nascent AVs are left of the broken line; mature forms are to the right. Nascent initial macro‐AVs (AVi) are formed from rough endoplasmic reticulum 33; nascent micro‐AVs are single‐walled vesicles, probably from smooth endoplasmic reticulum 89. They produce type A (autophagic) lysosomes after fusing with a type R (residual body) or another type A lysosome. The AVis mature to digestive vacuoles after acidification and subsequent fusion with type R lysosomes 34. End products of macro‐AVs include a few type A but mostly type R lysosomes. The point where endosomes join the lysosomal/vacuolar pathway is not fully settled and is not shown (see text for discussion). Electron microscopic illustrations: for AVi, see Schworer et al. 127 and Mortimore and Kadowaki 87; for type A and type R secondary lysosomes, see Mortimore et al. 89 and Surmacz et al. 136.



Figure 3.

Time course of macroautophagic vacuole (AV) formation and regression. A: Livers from normal fed rats were perfused in parallel without added amino acids and, at intervals, fixed for electron microscopy. Volume densities of initial (AVi), digestive (AVd), and total AVs were taken from Schworer et al. 127. B: Livers were perfused in parallel for 20 min without amino acids; at time zero, 10 x plasma amino acids were added. Volume densities were determined as in A. Inset: Semilogarithmic plot of the regression of total AV volume.

[From Schworer et al. 127 with permission.]


Figure 4.

Correlations between proteolysis, aggregate volumes of initial (AVi) and digestive (AVd) autophagic vacuoles, and the shift of β‐hexosaminidase from lysosomes to AVi during deprivation‐induced macroautophagy in perfused livers of fed rats. A: Relationship between accelerated long‐lived proteolysis (filled circles), and the above shift of β‐hexosaminidase (open circles), at various levels of plasma amino acids. The shift, which was determined in lysosomal‐vacuolar fractions separated in colloidal silica gradients 135, 136, is a measure of lysosomal‐AVi fusion 123. B: Correlation of AVi (open triangles), AVd (filled triangles), and the β‐hexosaminidase shift versus rates of deprivation‐induced proteolysis.

[From Surmacz et al. 134 with permission.]


Figure 5.

Relationship between long‐lived proteolysis and pools of intralysosomal degradable protein in rat liver over the full range of protein turnover. The quantity of valine residues in the protein pools per gram tissue from livers in various accelerated (open triangles), and basal (filled triangles) states of protein degradation was correlated with corresponding rates of proteolysis monitored from valine release. The above regression equation was y = ‐0.0002 + 0.0882x (r = 0.999), based on data from three studies 53, 89, 96 corrected for an intralysosomal pH of 4.5 93.



Figure 6.

Correlation between hepatic RNA degradation and lysosomal pools of degradable RNA. Livers from nonstarved rats, previously labeled with [14]orotic acid, were perfused with plasma amino acids over the full range of regulated RNA turnover (compare with Fig. 5). Breakdown of RNA in liver and in liver lysosomal particles was determined from [14]cytidine release as detailed by Heydrick et al. 48. Broken line displays total homogenate RNA breakdown (lysosome + cytosol); solid line gives total minus cytosolic breakdown rates. NML refers to homogenate fractions containing nuclei, mitochondria, and lysosomes 48.

[From Heydrick et al. 48 with permission.]


Figure 7.

Relationship between basal protein turnover and volume densities of type A and type R lysosomes during short‐term starvation in rat liver. Livers from fed and 48 h starved rats were perfused with 10 X plasma amino acids for the measurement of basal long‐lived proteolysis and stereological analysis of secondary lysosomes 89. Under‐ and over‐estimation of type A and type R elements, respectively, were corrected by multiplying the observed type A volumes 89 by 1.285, which equalized its slope to that of the total (see discussion in text); type R was then determined by subtracting type A from the total. Type A lysosomes were also assumed to be underestimated by ≈2% because of random sections through electron‐lucent zones. This correction increased the total ≈1% but did not affect type R. The type A volumes shown include closed invagination forms 89. IBW, initial body weight.



Figure 8.

Proteolytic dose‐response modes (H and L) to leucine in isolated hepatocytes from ad libitum‐fed rats. Responses to leucine and alanine were measured in 13 experiments, each on a different day. Responses to leucine (1X Leu + 1X Ala) on different days spontaneously fell into one of two randomly alternating modes, termed H and L.

[From Venerando et al. 143 with permission.]


Figure 9.

Proteolytic dose responses to regulatory amino acids. Livers from normal fed rats were perfused in the single‐pass mode with various regulatory amino acids (Reg AA) at fractions/multiples of their concentrations in a reference 1X plasma mixture. The 1X mixture was composed of the following (μM): Leu, 204; Gln, 716; Tyr, 98; Pro, 437; Met, 60; His, 92; Trp, 93 94, 143.

[From Mortimore et al. 94 with permission.


Figure 10.

Proteolytic dose responses to leucine, glutamine, and leucine + glutamine. Experiments were carried out as in Figure 9 except that livers were obtained from synchronously fed, 24 h starved rats. Molar values for leucine and glutamine on the abscissa (bottom) correspond to fractions/multiples of their concentrations in the reference plasma mixture (top) given in Figure 9. Values are means ± SE of 3 to 33 experiments, normalized to 100 g of initial body weight. AA, amino acid.

[From Miotto et al. 81 with permission.].


Figure 11.

Proteolytic dose responses to the standard complete amino acid (AA) mixture and to leucine + alanine. V represents proteolytic inhibition, expressed as nmol valine·min‐1 per liver (100 g of initial body weight); S denotes fractions/multiples of amino acids in the medium. In this plot, Vmax is shown as the V intercept. The apparent Km values are also relative (rel.) in that they are based on fractions/multiples of the molar values in the standard plasma mixture. A: Responses of livers from normal fed rats to the complete amino acid mixture. B: Responses of livers from synchronously fed, 24 h starved rats to the same mixture and to leucine + alanine.

[From Miotto et al. 81 with permission.]


Figure 12.

Nonreducing polyacrylamide gel electrophoresis showing a photolabeled plasma membrane protein of Mr ≈340,000 that had entered a 7.5% to 20% gradient gel. Labeling was strongly protected by 20 mM leucine in parallel runs. Fresh rat hepatocytes were photolyzed with (125I‐azidosalicylic acid) Leu7‐multiple antigen peptide ± 20 mM leucine, and the plasma membrane fraction was extracted with 2% sodium dodecyl sulfate for electrophoresis. No photolabeling was obtained with similar photoprobes constructed with valine or isoleucine.

[From Mortimore et al. 98 with permission.]


Figure 13.

Effects of 10‐9 M insulin on proteolytic dose responses to regulatory (Reg. AA) and complete plasma amino acid mixtures. In other respects, the experiments were the same as those in Figure 9.

[From Mortimore et al. 94 with permission.].


Figure 14.

Effect of 8 × 10‐9 M glucagon on the proteolytic dose‐response curve to regulatory amino acids (Reg. AA). The conditions otherwise were the same as those in Figure 9.

[From Mortimore et al. 94 with permission.]


Figure 15.

Alterations in the content of liver protein (upper panel), and in rates of protein synthesis and degradation (lower panel) during starvation and refeeding in the mouse. Rates of resident protein synthesis were determined as previously detailed 53; observed degradation rates were calculated by difference from the net changes in protein content in the upper panel. Observed degradation rates agreed closely with predicted rates based on stereologically determined volumes of digestive autophagic vacuoles and microautophagic vacuoles, the turnover of autophagic vacuoles, and estimates of cytoplasmic protein concentration using procedures and control stereological data from Blouin et al. 15.

[From Mortimore et al. 86 with permission.]
References
 1. Addis, T., D. D. Lee, W. Lew, and L. J. Poo. The protein content of the organs and tissues at different levels of protein consumption. J. Nutr. 19: 199–205, 1940.
 2. Addis, T., L. J. Poo, and W. Lew. The quantities lost by the various organs and tissues of the body during a fast. J. Biol. Chem. 115: 111–118, 1936.
 3. Ahlberg, J., A. Berkenstam, F. Henell, and H. Glaumann. Degradation of short and long lived proteins in isolated rat liver lysosomes. Effects of pH, temperature, and proteolytic inhibitors. J. Biol. Chem. 260: 5847–5854, 1985.
 4. Amenta, J. S., and S. C. Brocher. Mechanisms of protein turnover in cultured cells. Life Sci. 28: 1195–1208, 1981.
 5. Amherdt, M. V.. Harris, A. E. Renold, L. Orci, and R. H. Unger. Hepatic autophagy in uncontrolled experimental diabetes and its relationship to insulin and glucagon. J. Clin. Invest. 54: 188–193, 1974.
 6. Aplin, A., T. Jasionowski, D. L. Tuttle, S. E. Lenk, and W. A. Dunn, Jr.. Cytoskeletal elements are required for the formation and maturation of autophagic vacuoles. J. Cell. Physiol. 152: 458–466, 1992.
 7. Arstila, A. U., and B. F. Trump. Studies on autophagocytosis: the formation of autophagic vacuoles in the liver following glucagon administration. Am. J. Pathol. 53: 687–733, 1968.
 8. Ashford, T. P., and K. R. Porter. Cytoplasmic components in hepatic cell lysosomes. J. Cell Biol. 12: 198–202, 1962.
 9. Auteri, J. S., A. Okada, V. Bochaki, and J. F. Dice. Regulation of intracellular protein degradation in 1MR‐90 human diploid fibroblasts. J. Cell. Physiol. 115: 167–174, 1983.
 10. Balavoine, S., G. Feldmann, and B. Lardeux. Rates of RNA degradation in isolated rat hepatocytes. Effects of amino acids and inhibitors of lysosomal function. Eur. J. Biochem. 189: 617–623, 1990.
 11. Ballard, F. J., and J. M. Gunn. Nutritional and hormonal effects on intracellular protein catabolism. Nutr. Rev. 40: 33–42, 1982.
 12. Bleiberg‐Daniel, F., Y. Lamri, G. Feldmann, and B. Lardeux. Glucagon administration in vivo stimulates hepatic RNA and protein breakdown in fed and fasted rats. Biochem. J. 299: 645–649, 1994.
 13. Blommaart, E. F. C., U. Krause, J. P. M. Schellens, H. Vreeling‐Sindelárová, and A. J. Meijer. The phosphatidylinositol 3‐kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur. J. Biochem. 243: 240–246, 1997.
 14. Blommaart, E. F. C., J. J. Luiken, P. J. Blommaart, G. M. Van Woerkom, and A. J. Meijer. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J. Biol. Chem. 270: 2320–2326, 1995.
 15. Blouin, A., R. P. Bolender, and E. R. Weibel. Distribution of organelles and membranes between hepatocytes and non hepatocytes in the rat liver parenchyma. A stereological study. J. Cell Biol. 72: 441–455, 1977.
 16. Bolender, R. P., and E. P. Weibel. A morphometric study of the removal of phenobarbital‐induced membranes from hepatocytes after cessation of treatment. J. Cell Biol. 56: 746–761, 1973.
 17. Bond, J. S.. Failure to demonstrate increased protein turnover and intracellular proteinase activity in livers of mice with streptozotocin‐induced diabetes. Diabetes 29: 648–654, 1980.
 18. Buse, M. G., and S. S. Reid. Leucine: a possible regulator of protein turnover in muscle. J. Clin. Invest. 56: 1250–1261, 1975.
 19. Cardell, R. R., Jr.. Smooth endoplasmic reticulum in rat hepatocytes during glycogen deposition and depletion. Int. Rev. Cytol. 48: 221–279, 1977.
 20. Caro, L. H. P., P. J. A. M. Plomp, X. M. Leverve, and A. J. Meijer. A combination of intracellular leucine with glutamate or aspartate inhibits autophagic proteolysis in isolated rat hepatocytes. Eur. J. Biochem. 181: 717–720, 1989.
 21. Chua, B. H. L., R. L. Kao, D. E. Rannels, and H. E. Morgan. Inhibition of protein degradation by anoxia and ischemia in perfused rat hearts. J. Biol. Chem. 254: 6617–6623, 1979.
 22. Chua, B. H. L., C. A. Watkins, D. L. Siehl, and H. E. Morgan. Effects of epinephrine and glucagon on protein turnover in perfused rat heart. Federation Proc. 37: 1333A, 1978.
 23. Ciechanover, A., D. Finley, and A. Varshavsky. The ubiquitin‐mediated proteolytic pathway and mechanisms of energy‐dependent intracellular protein degradation. J. Cell. Biochem. 24: 27–53, 1984.
 24. Ciechanover, A. J., and A. L. Schwartz. The ubiquitin‐mediated proteolytic pathway: mechanisms of recognition of the proteolytic substrate and involvement in the degradation of native cellular proteins. In: Cellular Proteolytic Systems, edited by A. J. Ciechanover and A. L. Schwartz. New York: Wiley‐Liss, 1994 3–22.
 25. Conde, R. D., and O. A. Scornik. Role of protein degradation in the growth of livers after a nutritional shift. Biochem. J. 158: 385–390, 1976.
 26. Cuervo, A. M., S. R. Terlecky, J. F. Dice, and E. Knecht. Selective binding and uptake of ribonuclease A and glyceraldehyde‐3‐phosphate dehydrogenase by isolated rat liver lysosomes. J. Biol. Chem. 269: 26374–26380, 1994.
 27. Dämmrich, J., and U. Pfeifer. Acute effects of isoproterenol on cellular autophagy. Inhibition in myocardium but stimulation in liver parenchyma. Virchows Arch. 38: 209–218, 1981.
 28. de Duve, C., and R. Wattiaux. Functions of lysosomes. Annu. Rev. Physiol. 28: 435–492, 1966.
 29. Deter, R. L., P. Baudhuin, and C. de Duve. Participation of lysosomes in cellular autophagy induced in rat liver by glucagon. J. Cell Biol. 35: C11–C16, 1967.
 30. de Waal, E. J., H. Vreeling‐Sindelárová, J. P. Schellens, J. M. Hout‐kooper, and J. James. Quantitative changes in the lysosomal vacuolar system of rat hepatocytes during short‐term starvation. A morphometric analysis with special reference to macro‐ and microautophagy. Cell Tissue Res. 243: 641–648, 1986.
 31. Dice, F. J., and S. R. Terlecky. Selective degradation of cytosolic proteins by lysosomes. In: Cellular Proteolytic Systems, edited by A. J. Ciechanover and A. L. Schwartz. New York: Wiley‐Liss, 1994 p. 55–64.
 32. Dice, F. J., C. D. Walker, B. Byrne, and A. Cardiel. General characteristics of protein degradation in diabetes and starvation. Proc. Natl. Acad. Sci. U.S.A. 75: 2093–2097, 1978.
 33. Dunn, W. A., Jr.. Studies on the mechanism of autophagy: formation of the autophagic vacuole. J. Cell Biol. 110: 1923–1933, 1990.
 34. Dunn, W. A., Jr.. Studies on the mechanism of autophagy: maturation of the autophagic vacuole. J. Cell Biol. 110: 1935–1945, 1990.
 35. Epstein, D., S. Elias‐Bishko, and A. Hershko. Requirement for protein synthesis in the regulation of protein breakdown in cultured hepatoma cells. Biochemistry 14: 5199–5204, 1975.
 36. Fox, H. L., P. T. Pham, S. R. Kimball, L. S. Jefferson, and C. J. Lynch. Amino acid effects on the translational repressor 4E‐BP1 are mediated primarily by L‐leucine in isolated adipocytes. Am. J. Physiol. (Cell Physiol.) 275: C1232–C1238, 1998.
 37. Fulks, R. M., J. B. Li, and A. L. Goldberg. Effects of insulin, glucose, and amino acids on protein turnover in rat diaphragm. J. Biol. Chem. 250: 290–298, 1975.
 38. Garber, A. J., I. E. Karl, and D. M. Kipnis. Alanine and glutamine synthesis and release from skeletal muscle. IV. β‐Adrenergic inhibition of amino acid release. J. Biol. Chem. 251: 851–857, 1976.
 39. Goldberg, A. L.. The mechanisms and functions of ATP‐dependent proteases in bacterial and animal cells. Eur. J. Biochem. 203: 9–23, 1992.
 40. Gordon, P. B., H. Høyvik, and P. O. Seglen. Prelysosomal and lysosomal connections between autophagy and endocytosis. Biochem. J. 283: 361–369, 1992.
 41. Gordon, P. B., and P. O. Seglen. Prelysosomal convergence of autophagic and endocytic pathways. Biochem. Biophys. Res. Commun. 151: 40–47, 1988.
 42. Green, M., and L. L. Miller. Protein catabolism and protein synthesis in perfused livers of normal and alloxan‐diabetic rats. J. Biol. Chem. 235: 3202–3208, 1960.
 43. Grinde, B., and P. O. Seglen. Leucine inhibition of autophagic vacuole formation in isolated rat hepatocytes. Exp. Cell Res. 134: 33–39, 1981.
 44. Gropper, R., R. A. Brandt, S. Elias, C. F. Bearer, A. Mayer, A. L. Schwartz, and A. Ciechanover. The ubiquitin‐activating enzyme, E1, is required for stress‐induced lysosomal degradation of cellular proteins. J. Biol. Chem. 266: 3602–3610, 1991.
 45. Hallbrucker, C., S. vom Dahl, F. Lang, and D. Häussinger. Control of hepatic proteolysis by amino acids. The role of cell volume. Eur. J. Biochem. 197: 717–724, 1991.
 46. Hara, K., K. Yonezawa, Q.‐P. Weng, M. T. Koslowski, C. Belham, and J. Avruch. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF‐4E BP1 through a common effector mechanism. J. Biol. Chem. 273: 14484–14494, 1998.
 47. Häussinger, D., C. Hallbrucker, F. Lang, and W. Gerok. Cell swelling inhibits proteolysis in perfused rat liver. Biochem. J. 272: 239–242, 1990.
 48. Häussinger, D., W. Newsome, S. vom Dahl, B. Stoll, B. Noe, R. Schreiber, M. Wettstein, and F. Lang. The role of cell volume changes in metabolic regulation. Biochem. Soc. Trans. 22: 497–502, 1994.
 49. Henell, F., and H. Glaumann. Effect of leupeptin on the autophagic vacuolar system of rat hepatocytes. Correlation between ultrastructure and membrane and cytosolic proteins. Lab. Invest. 51: 46–56, 1984.
 50. Heydrick, S. J., B. R. Lardeux, and G. E. Mortimore. Uptake and degradation of cytoplasmic RNA by hepatic lysosomes: quantitative relationship to RNA turnover. J. Biol. Chem. 266: 8790–8796, 1991.
 51. Hirsimäki, P., A. U. Arstila, B. F. Trump, and L. Marzella. Autophagocytosis. In: Pathobiology of Cell Membranes, edited by A. U. Arstila and B. F. Trump. New York: Academic, 1983 vol. 3, 201–235.
 52. Hirsimäki, Y., and P. Hirsimäki. Vinblastine‐induced autophagocytosis: the effect of disorganization of microfilaments of cytochalasin B. Exp. Mol. Pathol. 40: 61–69, 1984.
 53. Hopgood, M. F., M. G. Clark, and F. J. Ballard. Protein degradation in hepatocyte monolayers. Effects of glucagon, adenosine 3':5'‐cyclic monophosphate and insulin. Biochem. J. 186: 71–79, 1980.
 54. Hutson, N. J., C. E. Lloyd, and G. E. Mortimore. Degradation of intra‐ and extracellular protein by livers of normal and diabetic mice: differential responses to starvation. Proc. Natl. Acad. Sci. U.S.A. 79: 1737–1741, 1982.
 55. Hutson, N. J., and G. E. Mortimore. Suppression of cytoplasmic protein uptake by lysosomes as the mechanism of protein regain in livers of starved‐refed mice. J. Biol. Chem. 257: 9548–9554, 1982.
 56. Izzo, J. L., and S. R. Glasser. Comparative effects of glucagon, hydrocortisone, and epinephrine on the protein metabolism of the fasted rat. Endocrinology 68: 189–198, 1961.
 57. Jefferson, L. S., D. E. Rannels, B. L. Munger, and H. E. Morgan. Insulin in the regulation of protein turnover in heart and skeletal muscle. Federation Proc. 33: 1098–1104, 1974.
 58. Kadowaki, M., and G. E. Mortimore. Mechanisms of autophagic proteolysis in permeabilized hepatocytes: involvement of GTP‐binding proteins at multiple steps. In: Proteolysis in Cell Functions, edited by V. K. Hopsu‐Havu, M. Jaervinen, and H. Kirscke, IOS, Press 1997 p. 381–387.
 59. Kadowaki, M., A. R. Pösö, and G. E. Mortimore. Parallel control of hepatic proteolysis by phenylalanine and phenylpyruvate through independent sites at the plasma membrane. J. Biol. Chem. 267: 22060–22065, 1992.
 60. Kadowaki, M., R. Venerando, G. Miotto, and G. E. Mortimore. De novo autophagic vacuole formation in hepatocytes permeabilized by Staphylococcus aureus α‐toxin: inhibition by nonhydrolyzable GTP analogs. J. Biol. Chem. 269: 3703–3710, 1994.
 61. Khairallah, E. A., and G. E. Mortimore. Assessment of protein turnover in perfused rat liver: evidence for amino acid compartmentation from differential labeling of free and tRNA‐bound valine. J. Biol. Chem. 251: 1375–1384, 1976.
 62. Kimball, S. R., R. L. Horetsky, and L. S. Jefferson. Implication of elF 2B rather than eIF 4E in the regulation of global protein synthesis by amino acids in L6 myoblasts. J. Biol. Chem. 273: 30945–30953, 1998.
 63. Knowles, S. E., and F. J. Ballard. Selective control of the degradation of normal and aberrant proteins in Reuber H35 hepatoma cells. Biochem. J. 156: 609–617, 1976.
 64. Kominami, E., S. Hashida, E. A. Khairallah, and N. Katunuma. Sequestration of cytoplasmic enzymes in autophagic vacuole‐lysosomal system induced by injection of leupeptin. J. Biol. Chem. 258: 6093–6100, 1983.
 65. Kopitz, J., G. Ø. Kisen, P. B. Gordon, P. Bohley, and P. O. Seglen. Nonselective autophagy of cytosolic enzymes by isolated rat hepatocytes. J. Cell Biol. 111: 941–953, 1990.
 66. Kosterlitz, H. W.. Effect of dietary protein on liver cytoplasm. Nature 154: 207–209, 1944.
 67. Kosterlitz, H. W., and I. D. Cramb. The effect of fasting on the protein content of the liver. J. Physiol. 102: 18P, 1943.
 68. Kovács, A. L., B. Grinde, and P. O. Seglen. Inhibition of autophagic vacuole formation and protein degradation by amino acids in isolated hepatocytes. Exp. Cell Res. 133: 431–436, 1981.
 69. Kovács, A. L., and P. O. Seglen. Inhibition of hepatocytic protein degradation by methylaminopurines and inhibitors of protein synthesis.
 70. Kovács, J., E. Fellinger, A. P. Kárpáti, A. L. Kovács, L. László, and G. Réz. Morphometric evaluation of the turnover of autophagic vacuoles after treatment with triton X‐100 and vinblastine in murine pancreatic acinar and seminal vesicle epithelial cells. Virchows Arch. 53: 183–190, 1987.
 71. Lardeux, B. R., S. J. Heydrick, and G. E. Mortimore. Rates of rat liver RNA degradation in vivo as determined from cytidine release during brief cyclic perfusion in situ. Biochem. J. 252: 363–367, 1988.
 72. Lardeux, B. R., S. J. Heydrick, and G. E. Mortimore. RNA degradation in perfused rat liver as determined from the release of [14C]cytidine. J. Biol. Chem. 262: 14507–14513, 1987.
 73. Lardeux, B. R., and G. E. Mortimore. Amino acid and hormonal control of macromolecular turnover in perfused rat liver: evidence for selective autophagy. J. Biol. Chem. 262: 14514–14519, 1987.
 74. Lawrence, B. P., and W. J. Brown. Autophagic vacuoles rapidly fuse with pre‐existing lysosomes in cultured hepatocytes. J. Cell Sci. 102: 515–526, 1992.
 75. Lenk, S. E., W. A. Dunn, Jr., J. S. Trausch, A. Ciechanover, and A. L. Schwartz. Ubiquitin‐activating enzyme is associated with maturation of autophagic vacuoles. J. Cell Biol. 118: 301–308, 1992.
 76. Leverve, X. M., L. H. Caro, P. J. Plomp, and A. J. Meijer. Control of proteolysis in perifused rat hepatocytes. FEBS Lett. 219: 455–458, 1987.
 77. Li, J. B., and L. S. Jefferson. Effect of isoproterenol on amino acid levels and protein turnover in skeletal muscle. Am. J. Physiol. 232 (Endocrinol. Metab. Gastrointest. Physiol. 1): E243–E249, 1977.
 78. Löw, P., F. J. Doherty, M. Sass, J. Kovács, R. J. Mayer, and L. Lászó. Immunogold localisation of ubiquitin‐protein conjugates in Sf9 insect cells. Implications for the biogenesis of lysosome‐related organelles. FEBS Lett. 316: 152–156, 1993.
 79. Luikens, J. J. P. F., M. van den Berg, J. C. Heikoop, and A. J. Meijer. Autophagic degradation of peroxisomes in isolated rat hepatocytes. FEBS Lett. 304: 93–97, 1992.
 80. Marty, F.. Cytochemical studies on GERL, provacuoles, and vacuoles in root meristematic cells of Euphorbia. Proc. Natl. Acad. Sci. U.S.A. 75: 852–856, 1978.
 81. Marzella, L., J. Ahlberg, and H. Glaumann. In vitro uptake of particles by lysosomes. Exp. Cell Res. 129: 460–466, 1980.
 82. Marzella, L., and H. Glaumann. Autophagy, microautophagy, and crinophagy as mechanisms for protein degradation. In: Lysosomes: Their Role in Protein Breakdown, edited by H. Glaumann and F. J. Ballard. London: Academic, 1987 p. 319–367.
 83. Meijer, A. J., L. A. Gustafson, J. J. Luiken, P. J. Blommaart, L. H. Caro, G. M. Van Woerkom, C. Spronk, and L. Boon. Cell swelling and the sensitivity of autophagic proteolysis to inhibition by amino acids in isolated rat hepatocytes. Eur. J. Biochem. 15: 449–454, 1993.
 84. Miotto, G., R. Venerando, K. K. Khurana, N. Siliprandi, and G. E. Mortimore. Control of hepatic proteolysis by leucine and isovaleryl‐L‐carnitine through a common locus: evidence for a possible mechanism of recognition at the plasma membrane. J. Biol. Chem. 267: 22066–22072, 1992.
 85. Miotto, G., R. Venerando, O. Marin, N. Siliprandi, and G. E. Mortimore. Inhibition of macroautophagy and proteolysis in the isolated rat hepatocyte by a nontransportable derivative of the multiple antigen peptide Leu8‐Lys4‐Lys2‐Lys‐βAla. J. Biol. Chem. 269: 25348–25353, 1994.
 86. Miotto, G., R. Venerando, and N. Siliprandi. Inhibitory action of isovaleryl‐L‐carnitine on proteolysis in perfused rat liver. Biochem. Biophys. Res. Commun. 158: 797–802, 1989.
 87. Mitch, W. E., and A. S. Clark. Specificity of the effects of leucine and its metabolites on protein degradation in skeletal muscle. Biochem. J. 222: 579–586, 1984.
 88. Mitchener, J. S., J. D. Shelburne, W. D. Bradford, and H. K. Hawkins. Cellular autophagocytosis induced by deprivation of serum and amino acids in HeLa cells. Am. J. Pathol. 83: 485–491, 1976.
 89. Mortimore, G. E., N. J. Hutson, and C. A. Surmacz. Quantitative correlation between proteolysis and macro‐ and microautophagy in mouse hepatocytes during starvation and refeeding. Proc. Natl. Acad. Sci. U.S.A. 80: 2179–2183, 1983.
 90. Mortimore, G. E., and M. Kadowaki. Autophagy: its mechanism and regulation. In: Cellular Proteolytic Systems, edited by A. J. Ciechanover and A. L. Schwartz. New York: Wiley‐Liss, 1994 p. 65–87.
 91. Mortimore, G. E., K. K. Khurana, and G. Miotto. Amino acid control of proteolysis in perfused livers of synchronously fed rats. J. Biol. Chem. 266: 1021–1028, 1991.
 92. Mortimore, G. E., B. R. Lardeux, and C. E. Adams. Regulation of microautophagy and basal protein turnover in rat liver: effects of short‐term starvation. J. Biol. Chem. 263: 2506–2512, 1988.
 93. Mortimore, G. E., and C. E. Mondon. Inhibition by insulin of valine turnover in liver: evidence for a general control of proteolysis. J. Biol. Chem. 245: 2375–2383, 1970.
 94. Mortimore, G. E., A. N. Neely, J. R. Cox, and R. A. Guinivan. Proteolysis in homogenates of perfused rat liver: responses to insulin, glucagon, and amino acids. Biochem. Biophys. Res. Commun. 54: 89–95, 1973.
 95. Mortimore, G. E., and A. R. Pösö. Intracellular protein catabolism and its control during nutrient deprivation and supply. Annu. Rev. Nutr. 7: 539–564, 1987.
 96. Mortimore, G. E., and A. R. Pösö. Lysosomal pathways in hepatic protein degradation: regulatory role of amino acids. Federation Proc. 43: 1289–1294, 1984.
 97. Mortimore, G. E., A. R. Pösö, M. Kadowaki, and J. J. Wert, Jr.. Multiphasic control of hepatic protein degradation by regulatory amino acids: general features and hormonal modulation. J. Biol. Chem. 262: 16322–16327, 1987.
 98. Mortimore, G. E., and C. M. Schworer. Induction of autophagy by amino acid deprivation in perfused rat liver. Nature 270: 174–176, 1977.
 99. Mortimore, G. E., and W. F. Ward. Internalization of cytoplasmic protein by hepatic lysosomes in basal and deprivation‐induced proteolytic states. J. Biol. Chem. 256: 7659–7665, 1981.
 100. Mortimore, G. E., J. J. Wert, Jr, and C. E. Adams. Modulation of the amino acid control of hepatic proteolysis by caloric deprivation: two modes of alanine co‐regulation. J. Biol. Chem. 263: 19545–19551, 1988.
 101. Mortimore, G. E., J. J. Wert, Jr., G. Miotto, R. Venerando, and M. Kadowaki. Leucine‐specific binding of photoreactive Leu7‐MAP to a high molecular weight protein on the plasma membrane of the isolated rat hepatocyte. Biochem. Biophys. Res. Commun. 203: 200–208, 1994.
 102. Mortimore, G. E., K. H. Woodside, and J. E. Henry. Compartmentation of free valine and its relation to protein turnover in perfused rat liver. J. Biol. Chem. 247: 2776–2784, 1972.
 103. Nair, K. S., D. Halliday, D. E. Matthews, and S. L. Welle. Hyperglucagonemia during insulin deficiency accelerates protein catabolism. Am. J. Physiol. 253 (Endocrinol. Metab. 16): E208–E213, 1987.
 104. Neely, A. N., J. R. Cox, J. A. Fortney, C. M. Schworer, and G. E. Mortimore. Alterations of lysosomal size and density during rat liver perfusion: suppression by insulin and amino acids. J. Biol. Chem. 252: 6948–6954, 1977.
 105. Neely, A. N., P. B. Nelson, and G. E. Mortimore. Osmotic alterations of the lysosomal system during rat liver perfusion: reversible suppression by insulin and amino acids. Biochim. Biophys. Acta 338: 458–472, 1974.
 106. Novikoff, A. B., and W. Y. Shin. Endoplasmic reticulum and autophagy in rat hepatocytes. Proc. Natl. Acad. Sci. U.S.A. 75: 5039–5042, 1978.
 107. Ogier‐Denis, E., A. Couvineau, J. J. Maoret, J. J. Houri, C. Bauvy, D. De Stefanis, C. Isidoro, M. Laburthe, and P. Codogno. A heterotrimeric G13‐protein controls autophagic sequestration in the human colon cancer cell line HT‐29. J. Biol. Chem. 270: 13–16, 1995.
 108. Ogier‐Denis, E., J. J. Houri, C. Baudy, and P. Codogno. Guanine nucleotide exchange on heterotrimeric G13 protein controls autophagic sequestration in HT‐29 cells. J. Biol. Chem. 271: 28593–28600, 1996.
 109. Ose, L., T. Ose, R. Reinersten, and T. Berg. Fluid endocytosis in isolated rat parenchymal and non‐parenchymal liver cells. Exp. Cell Res. 126: 109–119, 1980.
 110. Paavola, L. G.. The corpus luteum of the guinea pig. II. Cytochemical studies on the Golgi complex, GERL, and lysosomes in luteal cells during maximal progesterone secretion. J. Cell Biol. 79: 45–58, 1978.
 111. Paavola, L. G.. The corpus luteum of the guinea pig. III. Cytochemical studies on the Golgi complex and GERL during normal postpartum regression of luteal cells, emphasizing the origin of lysosomes and autophagic vacuoles. J. Cell Biol. 79: 59–73, 1978.
 112. Papadopoulos, T., and U. Pfeifer. Regression of rat liver autophagic vacuoles by locally applied cycloheximide. Lab. Invest. 54: 100–107, 1986.
 113. Patti, M.‐E., E. Brambilla, L. Luzi, E. J. Landaker, and C. R. Kahn. Bidirectional modulation of insulin action by amino acids. J. Clin. Invest. 101: 1519–1529, 1998.
 114. Peavy, D. E., J. M. Taylor, and L. S. Jefferson. Correlation of albumin production rates and albumin RNA levels in livers of normal, diabetic, and insulin‐treated diabetic rats. Proc. Natl. Acad. Sci. U.S.A. 75: 5879–5883, 1978.
 115. Pfeifer, U.. Cellular autophagy and cell atrophy in rat liver during long term starvation. Virchows Arch. 12: 195–211, 1973.
 116. Pfeifer, U.. Inhibition by insulin of the formation of autophagic vacuoles in rat liver. A morphometric approach to the kinetics of intracellular degradation by autophagy. J. Cell Biol. 78: 152–167, 1978.
 117. Pfeifer, U.. Morphological aspects of intracellular protein degradation: autophagy. Acta Biol. Med. Ger. 40: 1619–1624, 1981.
 118. Plomp, P. J., P. B. Gordon, A. J. Meijer, H. Høyvik, and P. O. Seglen. Energy dependence of different steps in the autophagic‐lysosomal pathway. J. Biol. Chem. 264: 6699–6704, 1989.
 119. Poli, A., P. B. Gordon, P. E. Schwarze, B. Grinde, and P. O. Seglen. Effect of insulin and anchorage on hepatocytic protein metabolism and amino acid transport. J. Cell Sci. 48: 1–18, 1981.
 120. Poole, B., and M. Wibo. Protein degradation in cultured cells. J. Biol. Chem. 248: 6221–6226, 1973.
 121. Pösö, A. R., and G. E. Mortimore. Requirement for alanine in the amino acid control of deprivation‐induced protein degradation in liver. Proc. Natl. Acad. Sci. U.S.A. 81: 4270–4274, 1984.
 122. Pösö, A. R., C. M. Schworer, and G. E. Mortimore. Acceleration of proteolysis in perfused rat liver by deletion of glucogenic amino acids: regulatory role of glutamine. Biochem. Biophys. Res. Commun. 107: 1433–1439, 1982.
 123. Pösö, A. R., J. J. Wert, Jr, and G. E. Mortimore. Multifunctional control by amino acids of deprivation‐induced proteolysis in liver: role of leucine. J. Biol. Chem. 257: 12114–12120, 1982.
 124. Punnonen, E. L., S. Autio, H. Kaija, and H. Reunanen. Autophagic vacuoles fuse with the prelysosomal compartment in cultured rat fibroblasts. Eur. J. Cell Biol. 6: 54–66, 1993.
 125. Rabkin, R., T. Tsao, J. D. Shi, and G. E. Mortimore. Amino acids regulate kidney cell protein breakdown. J. Lab. Clin. Med. 117: 505–513, 1991.
 126. Rannels, D. E., R. Kao, and H. E. Morgan. Effect of insulin on protein turnover in heart muscle. J. Biol. Chem. 250: 1694–1701, 1975.
 127. Rechsteiner, M., L. Hoffman, and W. Dubiel. The multicatalytic and 268 proteases. J. Biol. Chem. 268: 6065–6068, 1993.
 128. Rosa, F.. Ultrastructural changes produced by glucagon, cyclic 3'5'AMP and epinephrine on perfused rat livers. J. Ultrastruct. Res. 34: 205–213, 1971.
 129. Schwartz, A. L., R. A. Brandt, H. J. Geuze, and A. Ciechanover. Stress induced alteration in the autophagic pathway: relationship to ubiquitin system. Am. J. Physiol. 262 (Cell Physiol. 31): C1031–C1038, 1992.
 130. Schworer, C. M., and G. E. Mortimore. Glucagon‐induced autophagy and proteolysis in rat liver: mediation by selective deprivation of intracellular amino acids. Proc. Natl. Acad. Sci. U.S.A. 76: 3169–3173, 1979.
 131. Schworer, C. M., K. A. Shiffer, and G. E. Mortimore. Quantitative relationship between autophagy and proteolysis during graded amino acid deprivation in perfused rat liver. J. Biol. Chem. 256: 7652–7658, 1981.
 132. Seglen, P. O., and P. B. Gordon. 3‐Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc. Natl. Acad. Sci. U.S.A. 79: 1889–1892, 1982.
 133. Seglen, P. O., P. B. Gordon, and A. Poli. Amino acid inhibition of the autophagic/lysosomal pathway of protein degradation in isolated rat hepatocytes. Biochim. Biophys. Acta 630: 103–118, 1980.
 134. Seglen, P. O., and A. E. Solheim. Valine uptake and incorporation into protein in isolated rat hepatocytes. Nature of the precursor pool for protein synthesis. Eur. J. Biochem. 85: 15–25, 1978.
 135. Shiman, R., G. E. Mortimore, C. M. Schworer, and D. W. Gray. Regulation of phenylalanine hydroxylase activity by phenylalanine in vivo, in vitro, and in perfused rat liver. J. Biol. Chem. 257: 11213–11216, 1982.
 136. Solheim, A. E., and P. O. Seglen. Subcellular distribution of proteolytically generated valine in isolated rat hepatocytes. Eur. J. Biochem. 107: 587–596, 1980.
 137. Sommercorn, J. M., and R. W. Swick. Protein degradation in primary monolayer cultures of adult rat hepatocytes. J. Biol. Chem. 256: 4816–4821, 1981.
 138. Surmacz, C. A., A. R. Pösö, and G. E. Mortimore. Regulation of lysosomal fusion during deprivation‐induced autophagy in perfused rat liver. Biochem. J. 242: 453–458, 1987.
 139. Surmacz, C. A., J. J. Wert, Jr, and G. E. Mortimore. Metabolic alterations and distribution of rat liver lysosomes in colloidal silica. Am. J. Physiol. 245 (Cell Physiol. 14): C61–C67, 1983.
 140. Surmacz, C. A., J. J. Wert, Jr, and G. E. Mortimore. Role of particle interaction on distribution of liver lysosomes in colloidal silica, Am. J. Physiol. 245 (Cell Physiol. 14): C52–C60, 1983.
 141. Tam, J. P.. High‐density multiple antigenic‐peptide system for preparation of antipeptide antibodies. Methods Enzymol. 168: 7–15, 1989.
 142. Terlecky, S. R., and J. F. Dice. Polypeptide import and degradation by isolated lysosomes. J. Biol. Chem. 268: 23490–23495, 1994.
 143. Tischler, M. E., M. Desautels, and A. L. Goldberg. Does leucine, leucyl‐tRNA, or some metabolite of leucine regulate protein synthesis and degradation in rat skeletal and cardiac muscle? J. Biol. Chem. 257: 1613–1621, 1982.
 144. Tooze, J., M. Hollinshead, T. Ludwig, K. Howell, B. Hoflack, and H. Kern. In exocrine pancreas, the basolateral endocytic pathway converges with the autophagic pathway immediately after the early endosome. J. Cell Biol. 111: 329–345, 1990.
 145. Tsao, T. C., J. D. Shi, G. E. Mortimore, E. J. Cragoe, Jr., and R. Rabkin. Modulation of kidney cell protein degradation by insulin. J. Lab. Clin. Med. 116: 369–376, 1990.
 146. Vandenburgh, H., and S. Kaufman. Protein degradation in embryonic skeletal muscle. Effects of medium, cell type, inhibitors, and passive stretch. J. Biol. Chem. 255: 5826–5833, 1980.
 147. Venerando, R., G. Miotto, M. Kadowaki, N. Siliprandi, and G. E. Mortimore. Multiphasic control of proteolysis by leucine and alanine in the isolated rat hepatocyte. Am. J. Physiol. 266 (Cell Physiol. 35): C455–C461, 1994.
 148. Ward, W. F., J. R. Cox, and G. E. Mortimore. Lysosomal sequestration of intracellular protein as a regulatory step in hepatic proteolysis. J. Biol. Chem. 252: 6955–6961, 1977.
 149. Wert, J. J., Jr., G. Miotto, M. Kadowaki, and G. E. Mortimore. 4‐Amino‐6‐methylhept‐2‐enoic acid: a leucine analogue and potential probe for localizing sites of proteolytic control in the hepatocyte. Biochem. Biophys. Res. Commun. 186: 1327–1332, 1992.
 150. Wheatley, D. N.. Intracellular protein degradation: basis of a self‐regulating mechanism for the proteolysis of endogenous proteins. J. Theor. Biol. 107: 127–149, 1984.
 151. Woodside, K. H., and G. E. Mortimore. Suppression of protein turnover by amino acids in the perfused rat liver. J. Biol. Chem. 247: 6474–6481, 1972.
 152. Woodside, K. H., W. F. Ward, and G. E. Mortimore. Effects of glucagon on general protein degradation and synthesis in perfused rat liver. J. Biol. Chem. 249: 5458–5463, 1974.
 153. Yokota, S.. Formation of autophagosomes during degradation of excess peroxisomes induced by administration of dioctyl phthalate. Eur. J. Cell Biol. 61: 67–80, 1993.
 154. Young, V. R., and H. N. Munro. Nt‐Methylhistidine (3‐methylhistidine) and muscle protein turnover: an overview. Federation Proc. 37: 2291–2300, 1978.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Regulation of Protein Metabolism in Liver
 

How to Cite

Glenn E. Mortimore, Motoni Kadowaki. Regulation of Protein Metabolism in Liver. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 553-577. First published in print 2001. doi: 10.1002/cphy.cp070217