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Leucic Acid

Leucic acid (also known as α-hydroxyisocaproic acid or HICA) is a leucine metabolite touted to have anabolic properties. Although it appears to be effective following oral supplementation, comparisons to leucine or HMB do not exist.

Our evidence-based analysis on leucic acid features 14 unique references to scientific papers.

Kamal Patel
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Summary of Leucic Acid

Primary Information, Benefits, Effects, and Important Facts

Leucic acid (synonymous with the term α-hydroxyisocaproic acid and the latter's acronym HICA) is a metabolite of the branched chain amino acid known as leucine; leucine initially goes into one of two metabolic pathways (KIC or HMB) and then some of the KIC is further converted into HICA.

HICA is claimed to be an anti-catabolic and anabolic agent similar to HMB. The limited evidence that exists right now (literally one study in athletes and a mention of a pilot study conducted by the same researchers) suggests that there is benefit, but beyond needing replication this study is also confounded.

Although it would be imprudent to say that HICA is ineffective (which it does not appear to be) and similarly imprudent to say that it is worse than HMB or leucine, due to the lack of comparative data between HICA and HMB/leucine the question of 'which one to use' cannot be answered and we have no indication if HICA is better or worse than the other options.

HICA holds some promise for future research to tackle, but currently does not have enough evidence to support its usage as a supplement; it may simply be a more expensive and equally effective leucine.

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Things To Know & Note

Is a Form Of

Primary Function:

Also Known As

Alpha-Hydroxy-isocaproic acid, DL-alpha-Hydroxy-isocaproic acid, HICA

Do Not Confuse With

Leucine (parent amino acid), HMB (other metabolite)

Caution Notice

Examine.com Medical Disclaimer

How to Take Leucic Acid

Recommended dosage, active amounts, other details

The only human evidence currently uses a daily dose of 1,500mg HICA, split into three divided doses of 500mg. There is not enough evidence to suggest if this is the optimal dose nor is there evidence to assess the comparative potency of HICA against leucine or HMB supplementation.

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Human Effect Matrix

The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects leucic acid has on your body, and how strong these effects are.
Grade Level of Evidence
Robust research conducted with repeated double-blind clinical trials
Multiple studies where at least two are double-blind and placebo controlled
Single double-blind study or multiple cohort studies
Uncontrolled or observational studies only
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Outcome Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
Notes
grade-c
Lean Mass
Minor - See study
An increase in lean mass has been noted in the legs of soccer players to the degree of 0.4kg over 4 weeks; this study currently stands alone
grade-c
Muscle Soreness
Minor - See study
A decrease in muscle soreness has been noted in the one study conducted in athletes (when measured at week 4 only) to the degree of around 23%, but muscle soreness was not overly high in the study to begin with
grade-c
Weight
Minor - See study
The lone study using leucic acid in athletes has noted a minor but statistically significant increase in weight, attributable to lean mass (muscle plus water; bone mass unchanged)
grade-c
Anaerobic Running Capacity
- - See study
No significant influence on anaerobic running capacity
grade-c
Bone Mineral Density
- - See study
No significant alterations in bone mineral density
grade-c
Fat Mass
- - See study
No significant interaction between leucic acid and body fat has yet to be detected
grade-c
Power Output
- - See study
Power output as assessed by jumping tasks and weightlifting is unaffected

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Scientific Research on Leucic Acid

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1Sources and Structure

1.1Structure

Leucic acid (synonyms of DL-α-hydroxy-isocaproic acid (HICA) and DL-2-hydroxy-4-methylvaleric acid), commonly referred to as its acronym HICA, is a leucine metabolite.

Parent leucine is known to be degraded into its primary metabolite which is the keto acid ketoisocaproic acid (called KIC or KICA) and the keto acid tends to exist in equilibrium with leucine.[1] The same enzyme that mediates conversion of leucine to KIC[2] is also required for conversion into HICA, as HICA is a reduction production of KIC via the Hydroxyisocaproic acid dehydrogenase enzyme.[3] Anything that possesses the Hydroxyisocaproic acid dehydrogenase enzyme can produce HICA, and this seems to be humans (mostly in the liver) and select bacteria of the lactobacillus family.[4]

HICA is thought to be relevant since it can exert anti-catabolic effects at physiological concentrations while KIC cannot,[5] KIC requiring an infusion.[6] This suggests that the hydroxy leucine metabolites may be more potent than the keto acid metabolites.

HICA is a minor leucine metabolite that possesses anticatabolic properties. It is produced from the major leucine metabolite (KIC) but in smaller amounts

HICA is found circulating in the blood naturally (at around 0.25+/-0.02mmol/L, which is approximately 1% that of KIC at 21.6+/-2.1mmol/L[7]) and it is not bound to plasma proteins such as albumin.[7] It is detectable in urine[8] and other biological fluid as well.[9][10]

The primary keto metabolite of leucine, KIC, is approximatley 100-fold more prominent in serum relative to the hydroxy metabolite HICA

1.2Sources

Some foods appear to be naturally occurring sources of HICA, including:

Food sources are likely due to either fermentation (wine and sake) or bacterial incubation (cheeses) using lactic acid producing bacteria such as Lactobacillus plantarum or lactobacillus casei to promote conversion.[3][13]

Some foods have a quite minor HICA content, which is likely related to fermentation or bacteria

2Skeletal Muscle and Performance

2.1Interventions

583mg of a sodium salt of HICA (500mg HICA equivalent) thrice daily (1,500mg total) for 4 weeks in trained soccer athletes undergoing routine exercise protocols noted that while there were no differences in fat mass the HICA group experienced an increase in lean mass (0.4kg in lower limbs; no change in upper body) while placebo experiencing a small decrease (0.15kg in lower limbs).[14] This study had a dietary calorie and protein intake of 2,672+/-564kcal and 119+/-37g, respectively, and the authors made mention of a pilot study in wrestlers where 6 weeks of a similar dose failed to promote lean mass accrual.[14]

A reduction in soreness (DOMS) has been reported with 1,500mg HICA daily in soccer players after 4 weeks by 23% (and stated to have occurred in a pilot study by the same authors when testing in wrestlers), and subjective training alertness appeared to be somewhat improved (significantly higher at week two, trending higher otherwise).[14]

Appears to be somewhat effective at reducing muscular soreness and perhaps increasing lean mass, but overall has a low amount of evidence (possibly confounded as the researchers also hold patents) and there are no comparative studies of HICA against leucine or HMB

3Inflammation and Immunology

3.1Bacteria

HICA appears to have anti-bacterial properties in vitro that are fairly broad, having an IC50 of less than 4.5mg/mL on 16 bacterial strains (excluding Lactobacillus rhamnosus at 9mg/mL).[4]

Preliminary evidence that HICA could be antibacterial in the strains of bacteria that do not otherwise produce HICA (due to lacking the Hydroxyisocaproic acid dehydrogenase enzyme), although it is too preliminary to suggest what supplementation of HICA could do

References

  1. ^ Staten MA, Bier DM, Matthews DE. Regulation of valine metabolism in man: a stable isotope study. Am J Clin Nutr. (1984)
  2. ^ BLANCHARD M, GREEN DE, et al. l-Hydroxy acid oxidase. J Biol Chem. (1946)
  3. ^ a b Broadbent JR, et al. Overexpression of Lactobacillus casei D-hydroxyisocaproic acid dehydrogenase in cheddar cheese. Appl Environ Microbiol. (2004)
  4. ^ a b Sakko M, et al. 2-Hydroxyisocaproic acid (HICA): a new potential topical antibacterial agent. Int J Antimicrob Agents. (2012)
  5. ^ Mortimore GE, et al. Multiphasic control of hepatic protein degradation by regulatory amino acids. General features and hormonal modulation. J Biol Chem. (1987)
  6. ^ Tischler ME, Desautels M, Goldberg AL. Does leucine, leucyl-tRNA, or some metabolite of leucine regulate protein synthesis and degradation in skeletal and cardiac muscle. J Biol Chem. (1982)
  7. ^ a b Hoffer LJ, et al. Alpha-keto and alpha-hydroxy branched-chain acid interrelationships in normal humans. J Nutr. (1993)
  8. ^ Lancaster G, Mamer OA, Scriver CR. Branched-chain alpha-keto acids isolated as oxime derivatives: relationship to the corresponding hydroxy acids and amino acids in maple syrup urine disease. Metabolism. (1974)
  9. ^ Jakobs C, Sweetman L, Nyhan WL. Hydroxy acid metabolites of branched-chain amino acids in amniotic fluid. Clin Chim Acta. (1984)
  10. ^ Mamer OA, Laschic NS, Scriver CR. Stable isotope dilution assay for branched chain alpha-hydroxy-and alpha-ketoacids: serum concentrations for normal children. Biomed Environ Mass Spectrom. (1986)
  11. ^ Some Volatile Components of Vitis Vinifera Variety White Riesling. 2. Organic Acids Extracted from Wine.
  12. ^ PROCESS FOR ENHANCING A FRESH CHEESE FLAVOR IN FOODS.
  13. ^ Lerch HP, et al. Cloning, sequencing and expression in Escherichia coli of the D-2-hydroxyisocaproate dehydrogenase gene of Lactobacillus casei. Gene. (1989)
  14. ^ a b c Effects of alfa-hydroxy-isocaproic acid on body composition, DOMS and performance in athletes.

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This page is regularly updated, to include the most recently available clinical trial evidence.

Each member of our research team is required to have no conflicts of interest, including with supplement manufacturers, food companies, and industry funders. The team includes nutrition researchers, registered dietitians, physicians, and pharmacists. We have a strict editorial process.

This page features 14 references. All factual claims are followed by specifically-applicable references. Click here to see the full set of references for this page.

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