The fasting state and the acidotic state provide examples of the inter-organ flux of amino acids necessary to maintain the free amino acid pool in the blood and supply tissues with their required amino acids, and to maintain physiological pH. During an overnight fast, protein synthesis in the liver and other tissues continues, but at a diminished rate compared to the postprandial state (after eating). Net degradation of labile protein occurs in skeletal muscle, which contains the body’s largest protein mass, and in other tissues. The net degradation of protein affects functional proteins, such as skeletal muscle myosin, which are sacrificed to meet more urgent demands for amino acids in other tissues, and to provide carbon skeletons for gluconeogenesis by the liver to meet the needs for glucose, particularly of brain and red blood cells.

The pattern of inter-organ flux of amino acids is affected by conditions that change the supply of fuels (for example the overnight fast, a mixed meal, a high protein meal), and by conditions that increase the demand for amino acids (metabolic acidosis, surgical stress, traumatic injury, burns, wound healing, and sepsis). The flux of amino acid carbon and nitrogen in these different conditions is dictated by several factors:

  1. Ammonia (NH4+) is toxic. Consequently, it is transported between tissues as alanine or glutamine. Alanine is the principal carrier of amino acid nitrogen from other tissues back to the liver, where the nitrogen is converted to urea and subsequently excreted into the urine by the kidneys. The amount of urea synthesized is proportional to the amount of amino acid carbon that is oxidized as fuel.
  2. The pool of glutamine in the blood serves several essential metabolic functions. It provides ammonia for excretion of protons in the urine as NH4+. It serves as a fuel for the gut, the kidney, and the cells of the immune system. Glutamine is also required by the cells of the immune system and other rapidly dividing cells in which its amide group serves as the source of nitrogen for biosynthetic reactions; glutamine is a major donor of nitrogen for biosynthetic reactions. In the brain, the formation of glutamine from glutamate and NH4+ provides a means of removing ammonia and of transporting glutamate between cells in the brain. The utilization of blood glutamine is prioritized. During metabolic acidosis the kidney becomes the predominant site of glutamine uptake, at the expense of glutamine utilization in other tissues. On the other hand, during sepsis, cells involved in the immune response (macrophages, hepatocytes) become the preferential sites of glutamine uptake.
  3. The branched chain amino acids — valine, leucine, isoleucine — form a significant portion of the average protein, and can be converted to TCA cycle intermediates and utilized as fuels by almost all tissues. They are also the major precursors of glutamine. Except for the branched chain amino acids and alanine, aspartate, and glutamine, the catabolism of amino acids occurs principally in the liver.
  4. Amino acids are major gluconeogenic substrates, and most of the energy obtained from their oxidation is derived from oxidation of the glucose formed from their carbon skeletons. A much smaller percentage of amino acid carbon is converted to acetyl CoA or to ketone bodies and oxidized. The utilization of amino acids for glucose synthesis for the brain and other glucose-requiring tissues is subject to the hormonal regulatory mechanisms of glucose homeostasis.
  5. The relative rates of protein synthesis and degradation — protein turnover — determine the size of the free amino acid pools available for the synthesis of new proteins and for other essential functions. For example, the synthesis of new proteins to mount an immune response is supported by the net degradation of the proteins in the body.
Skeletal Muscle
The release of amino acids from skeletal muscle is stimulated during an overnight fast by the decrease of insulin and increase of glucocorticoid levels in the blood. Insulin promotes uptake of amino acids and the general synthesis of proteins. The fall in blood insulin during an overnight fast results in net proteolysis and release of amino acids, because the equilibrium between protein synthesis and protein degradation is shifted toward degradation.
amino Acids Released from Forearm

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Glutamine In The Kidney: Glutaminase

muscle Glutamine Production 1

Glutamine is the source of ammonia to buffer excess protons for excretion in the urine. Glutaminase releases the amide nitrogen. In acidoses the activity of renal Glutaminase is increased.

Glutamate In The Kidney: Glutamate Dehydrogenase

muscle Glutamine Production 2

Glutamate Dehydrogenase releases the amino nitrogen. In acidosis renal Glutamate Dehydrogenase activity is increased.

Proton Elimination Into The Proximal Tubule Urine

muscle Glutamine Production 3

Excess protons are pumped across the renal tubule cell membrane into the lumen of the proximal tubule in exchange for sodium ions.

Ammonia Diffuses Across The Renal Tubule Plasma Membrane

muscle Glutamine Production 4

α-Ammonium ions derived from glutamine by Glutaminase and Glutamate Dehydrogenase are in equilibrium with ammonia. Ammonia, but not the ammoniuim ion diffuses across the renal tubule cell plasma membrane into the lumen of the proximal tubule.

Ammonia Buffers The Excess Protons

muscle Glutamine Production 5

Excess protons in the proximal tubule urine combine with the ammonia and the resulting ammonium ion is excreted.

One of the primary roles of amino acid nitrogen is to provide ammonia in the kidney for the excretion of excess protons in the urine to alleviate acidosis. The rate of uptake of glutamine, the ammonia donor, from the blood and its utilization by the kidney depends mainly on the amount of acid that must be excreted to maintain a normal pH in the blood. During acidosis excretion of NH4+ increases several fold.
Excreted Compounds
Kidney Major Fuels*Glucose used in the renal medulla is produced in the renal cortex
Note the difference in NH4+ excretion and the use of glutamine by the kidney between the normal state and acidosis

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Fate of α-Ketoglutarate In The Kidney

Ketoglutarate in the Kidney 1

α-ketoglutarate resulting from the deamidation and deamination of glutamine enters the TCA cycle, where it loses a CO2 as it is converted to a four-carbon TCA cycle intermediate.

Fate of α-Ketoglutarate In The Kidney

Ketoglutarate in the Kidney 2

To be oxidized completely for the production of energy, it must first exit the TCA cycle, which it can do via mitochondrial malic enzyme (decarboxylating malate dehydrogenase).

Fate of α-Ketoglutarate In The Kidney

Ketoglutarate in the Kidney 3

The resulting pyruvate can be converted to acetyl CoA (pyruvate dehydrogenase), which can enter the TCA cycle to be oxidized completely to CO2. Glutamine is normally used as a source of energy for the kidney, and even more so during fasting or acidosis.

Fate of α-Ketoglutarate In The Kidney

Ketoglutarate in the Kidney 4

The pyruvate could be converted to lactate (lactate dehydrogenase) and returned to the blood, or

Fate of α-Ketoglutarate In The Kidney

Ketoglutarate in the Kidney 5

because, like the liver, the kidney is a glucogenic organ, the pyruvate could be converted to oxaloacetate (pyruvate carboxylase) and subsequently to phosphoenolpyruvate (phosphoenolpyruvate carboxykinase) and then to glucose.

Fate of α-Ketoglutarate In The Kidney

Ketoglutarate in the Kidney 6

Excess nitrogen could be donated in a transamination reaction to pyruvate, converting it to alanine, which could carry the excess nitrogen to the liver for disposal in urea.

Fate of α-Ketoglutarate In The Kidney

Ketoglutarate in the Kidney 7

Cortisol, a glucocorticoid — it causes glucose levels to raise — secreted in response to chronic stress, induces the transcription of phosphoenolpyruvate carboxykinase (in both the kidney and the liver), which converts oxaloacetate to phosphoenolpyruvate that is used for the synthesis of glucose.

Glutamine is used as a fuel by the kidney in the normal fed state, and to a greater extent during fasting and metabolic acidosis. After deamination by glutaminase and glutaminate dehydrogenase the resulting α-ketoglutarate can be used as a fuel by the kidney and is oxidized to CO2, converted to glucose for use in cells in the renal medulla, or converted to alanine to return ammonia to the liver for urea synthesis and excretion.
NOTE: cells of the renal medulla have a relatively high dependence on anaerobic glycolysis due to their lower oxygen supply and mitochondrial capacity; the lactate released from anaerobic glycolysis in these cells is taken up and oxidized in the renal cortical cells, which have a higher mitochondrial capacity and greater blood supply.

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Cortisol Activation of PEPCK Gene Transcription

Cortisol PEPCK Gene Transcription 1

The unliganded glucocorticoid (GR) receptor is located in the cytosol and inactive.

Glucocorticoid Receptor: Cortisol Binds

Cortisol PEPCK Gene Transcription 2

Cortisol, a glucocorticoid, binds the glucocorticoid receptor, causing it to dimerize and become active.

Glucocorticoid Receptor: Transfer to Nucleus

Cortisol PEPCK Gene Transcription 3

The active glucocorticoid receptor bound to cortisol enters the nucleus and binds to the Glucacorticoid Response Element [GRE] in glucocorticoid-regulated genes.

Glucocorticoid Receptor: PEPCK Gene Activation

Cortisol PEPCK Gene Transcription 4

The gene for phosphophoenylpyruvate carboxykinase contains a glucacorticoid response element that binds the liganded glucicorticoid receptor, which activates its transcription in both the kidney and liver, causing glucose synthesis in both tissues (gluconeogenesis).

The liver is the major site of amino acid catabolism. It converts amino acid ammonia, ammonium ion, to urea for excretion. Normally it converts most of the amino acid carbon skeletons to intermediates of the TCA cycle or pyruvate, which are major source of its energy. During prolonged hypoglycemia, the liver derives a major source of its energy from the β-oxidation of fatty acids. The liver uses the acetyl CoA end product of β-oxidation to synthesize ketone bodies, which it releases into the blood as a source of energy for extra-hepatic tissues that contain mitochondria, particularly the brain. Amino acid carbon skeletons generated in the liver during hypoglycemia are not required for liver energy generation, but instead become available for the synthesis of glucose.

Glucagon signaling in the liver results in an increase in the number of liver amino acid transporters, particularly alanine transporters, allowing the liver to take an increased number of amino acids from the blood, which are supplied by the inreased protein degradation in extra-hepatic tissues in response to cortisol signaling. Glutamine is spared degradation in the liver because signaling by cortisol, which is secreted in response to several chronic stresses, including hypoglycemia and acidosis, downregulates glutaminase in the liver periportal cells. Thus, the glutamine, a significant nitrogen donor, becomes available to whichever cells respond to any particular chronic stress, with respect to acidosis, the kidney gets most of the glutamine, but, for examaple significant infections, cells of the immune system get most of the glutamine as the increase in number to eliminate infectious agents.