Valine

Valine is one of the essential amino acids (EAAs), and belongs to the subclass of branched chain amino acids with the other two EAAs leucine and isoleucine; similar to the latter two, valine is in this group due to having a branched side-chain which is common to these three amino acids and no others.

Valine is metabolized reversibly into the alpha-keto derivative known as 2-ketoisovalerate (via the branched-chain aminotransferase enzyme) and then irreversibly into isobutyryl-CoA (via the rate-limiting branched-chain α-keto acid dehydrogenase enzyme).^[1]

Valine (both L and D isomers) are also known as a glucogenic amino acid (similar to isoleucine but not leucine) and can be converted into glucose in the liver.^[2][3] The methyl carbons of valine appear to be utilized to create glucose and subsequently glycogen, and may produce some carbon dioxide as a byproduct.^[4] This oxidation into glucose, similar to isoleucine, is increased following injury to skeletal muscle.^[5]

As valine is an essential amino acid, it can have a deficiency state.

A dietary elimination of valine in rats is able to induce lipid droplet formation in the liver (indicative of fatty liver formation)^[6] with other symptoms of valine depletion including leukopenia, hypoalbuminemia, hair loss, and weight loss.^[7] Restricting valine intake in swine tends to reduce food intake, which is aggravated with excess dietary leucine.^[8]

However, valine depleted diets have been found to have a role in reducing tumor growth in rats.^[7][6] It is thought that delivering a small amount of valine directly to the portal vein of the liver (practical only in clinical settings) may prevent fatty liver.^[9]

Due to the link between athletes and Amyotrophic lateral sclerosis (ALS, albeit somewhat unreliable of an association that is still up for debate^[10] with both positive^[11][12] and null^[13] evidence) investigation into agents possibly used by these athletes were conducted and BCAAs suspected.

The epidemiological link between ALS and athletes is somewhat weak and inconsistent, and even then the link between ALS and BCAA supplementation (hypothesized to be more commonly occurring in athletes) is currently unsupported

Valine has been noted to (in vitro) cause dose-dependent hyperexcitability in stimulated neurons (10-300μM incubation for 6 days) which is abolished by rapamycin (mTOR inhibitor) and suppress with Riluzole (sodium channel blocker),^[14] and this was similar to the other two BCAAs but not amino acids without a branched side-chain (alanine and phenylalanine). As hyperexcitability of neurons is a pathological feature of ALS in humans^[15][16] and of the mouse model which mimicks ALS (the G93A model^[17][18]), it was thought that this induced hyperexcitability could be a mechanism of action. BCAA-induced hypersensitivity also appeared to be sodium channel dependent, and occurred in mice (B6SJL strain) raised from birth with 2.5% of the diet as BCAAs (1:1:1 ratio).^[14]

Both in vitro and mouse models of BCAA incubation/supplementation fail to find alterations in resting membrane potential.^[14]

It is plausible that BCAAs may increase neuronal excitation via mTOR dependent means, but the in vitro evidence used quite high concentrations while the mouse model was conducted from birth (which is usually more sensitive to neurological effects but may not accurately represent a non-infant consuming the agent). More research on this topic is needed

1mM valine incubated with a muscle cell not in the presence of insulin does not appear to modify glucose uptake,^[19] yet oral supplementation of 0.3g/kg in rats prior to a glucose tolerance test causes an elevated level of glucose in serum 30 minutes into the test (but not 60-120 minutes) while leucine caused an increase at 60-120 minutes.^[19]

Elsewhere in humans (either with type II diabetes or impaired glucose tolerance) intravenous valine has been noted to reduce fractional clearance rate of glucose.^[20]

May induce a transient state of insulin resistance, similar to leucine but quicker acting

Valine has been noted to increase insulin secretion from the pancreas, but is approximately 3-9% (health persons and those with impaired glucose tolerance) as potent as glucose itself and weaker than L-arginine (46-61%), but in type II diabetics increases to 47% (Arginine at 180%).^[20]

Valine may increase insulin secretion, but it is fairly weak in doing so

Valine appears to promote glycogen synthesis in muscle cells, but to a lesser degree (about 61% as potent) as leucine supplementation.^[19]

A study in neurons where the effects of valine were abolished by rapamycin suggest that valine can activate mTOR^[14] and an increased protein content of P90S6K has been noted in these neurons incubated with valine (without rapamycin);^[14] this protein is downstream of mTOR and activated when mTOR is activated.^[21]

Other studies in adipocytes have noted either inactivity^[22] or activity significantly less potent than leucine in activatin mTOR, where 8mM is required for activation (leucine significantly active at 1mM)^[23] and valine possessing an EC₅₀ value of greater than 10mM.^[23]

In dendritic cell cultures (antigen presenting cells) removal of BCAAs or valine (but not leucine or isoleucine) from the medium impairs maturation, CD83 receptor expression, and the ability of dendritic cells to stimulate monocytes.^[24]

Supplementation of L-Valine to healthy controls and cirrhotic patients (from hepatitis C) experience increase dendritic cell and monocyte interaction as well as increased IL-12 secretion^[24] which has been noted to apply to persons with advanced cirrhosis^[25] which is known to have impaired dendritic function.^[26]

Valine supplementation is possibly immunostimulatory

One case study exists in a woman with advanced liver cirrhosis associated with hepatitis C where supplemental L-valine (3g a day for four weeks, then increasing sequentially by 3g every four weeks until 12g daily was consumed) was able to suppress serum HCV and α-fetoprotein (AFP); this suggests that valine may have an antiviral role.^[27]