Tetradecyl Thioacetic Acid

Tetradecyl thioacetic acid (TTA) is a nondietary fatty acid which belongs to the omega-3 class, but is also considered a thia fatty acid as it possesses a sulfur group in the fatty acid chain. It does not have the ability to be β-oxidized due to this, and does not confer to bodily energy requirements.

In isolated human liver cells 10-30µM TTA is able activate PPARα and PPARδ with preference for PPARα activation,^[1] while PPARγ was not significantly influenced until a concentration of 75µM (and even then, it was only 60% potency of the reference drug rosiglitazone).^[1] PPARδ activation has also been noted in myotubes by increasing fatty acid oxidation with a similar potency to the research standard GW501516^[1] increasing the downstream targets of CPT-1 (almost 2-fold) and CD36/FAT (almost 3-fold) relative to control,^[1] and activation of PPARδ is thought to also be a target of fat metabolism in liver cells as deleting PPARα is not sufficient to ablate the efficacy of TTA while increasing the protein content of PPARδ increases the in vitro efficacy of TTA in liver cells.^[2]

Due to oral supplementation of TTA in humans either significantly^[1][3] or nonsignificantly^[4] reducing total lipid levels in the blood (thought to reflect baseline lipid concentrations), it is thought that the above mechanisms are relevant to supplementation of TTA.

Tetradecylthioacetic acid (TTA) appears to be a ligand and activator for PPARs, specifically the alpha and delta subsets. When activated, these receptors are thought to positively mediate the oxidation of fatty acids in both liver and muscle cells

Tetradecyl thioacetic acid (TTA) has been noted to reduce the secretion of triglycerides rich lipoproteins^[5] from an intestinal cell line known as Caco-2 when coincubated with fatty acids.^[5] Unlike in liver cells where the reduction in triglyceride secretion appears to be secondary to increasing fatty acid oxidation,^[6][6] the two phenomena appear to be independent of one another in Caco-2 cells.^[5]

TTA itself is absorbed into Caco-2 cells^[5][7] and despite the reduced secretion of triglyceride rich lipoproteins with TTA relative to oleic acid they have comparable rates of incorporation; there does not appear to be marked accumulation of TTA-enriched lipoproteins within the cell, thought to be due to TTA more readily forming complexes with phospholipids.^[5] TTA is known to be ultimately absorbed from the intestines due to it being detected in serum following supplementation, although the exact bioavailability is unknown.

Following oral ingestion, Tetradecyl thioacetic acid (TTA) appears to have a lag time of approximately 90 minutes where minimal to no TTA is detected in the blood followed by rapid detection in the blood.^[4] Following this TTA appears to be detectable in the blood at median peak values (estimated C_max values) of 2.9mg/L (200mg), 11.5mg/L (600mg), and 11mg/L (1,000mg) at variable mean T_max values of 2.5-4.5 hours following oral administration; all values had a high range of individual variability.^[4]

TTA can be detected in the blood following a single dose, but appears to have a lag time before absorption and a fairly variable peak concentration and time to reach peak concentration between subjects.

Chronic loading for seven days at three doses (200mg, 600mg, and 1,000mg) all demonstrate increases in serum TTA with subsequent doses, suggesting a loading effect due to incomplete drug elimination within 24 hours.^[4] A dose-dependent relationship is more apparent after a week, where the doses reach circulating plasma concentrations of 4mg/L, 9mg/L, and 14mg/L in the 200mg, 600mg, and 1,000mg groups respectively.^[4]

When looking at total blood lipids, TTA appears to increase from nonexistent up to 0.44+/-0.03% of blood lipids following a month of 1,000mg supplementation^[3] whereas the major metabolite of TTA 1n-8 comprises 0.14+/-0.03% of total blood lipids.^[3]

Chronic loading is similar to acute loading, although a dose-dependent effect is more apparent. The maximum concentration seem with acute usage at 1,000mg does not appear to be increased further with chronic usage.

TTA has a volume of distribution ranging from 52.3 to 84.3 L based on oral dose and interindividual differences, which suggest binding to the lipid compartment of the blood.^[4]

In serum with chronic loading of 600mg or 1,000mg, a delta-9-desaturase derivative of TTA has been detected (TTA 1n-8) suggesting that it is metabolized via this enzyme in humans.^[4]

Due to being a sulfated fatty acid, TTA cannot be metabolized by the process of β-oxidation for utilization as energy.^[8][9]

After one week of supplementing tetradecyl thioacetic acid (TTA) in the range of 200-1000mg, TTA was still found in the body by day 14 (one week of cessation) but was not detectable after one month after the start of the study (three weeks of cessation).^[4] Approximately 80% of circulating TTA is eliminated by 1 week of cessation, returning to baseline 3 weeks after cessation.^[4]

Rate of clearance was estimated to be 4.1-5.6L per hour based on oral doses of 200,600, and 1000mg.^[4] The estimated half-life of TTA following oral administration in humans is between 8.9 and 14 hours.^[4]

TTA appears to be slowly metabolized and has a half-life reaching about half a day, indicating that a single oral dose would influence the body for over a 24 hour period. TTA may still be detectable in the blood following a week cessation from the supplement, but is no longer detectable after three weeks.

Tetradecyl thioacetic acid (TTA) is known to attenuate the stimulation of triglyceride-rich lipoprotein secretion from other fatty acids such as oleic acid when coincubated in vitro in intestinal cells^[5] and in liver cells,^[6] suggesting that there may be an inhibitory effect on the release of circulating fatty acids from these two organs that may contribute to the hypolipidemic effects observed with TTA ingestion.

There is a possible inhibitory effect on complete fatty acid absorption associated with TTA supplementation, although this is not related to an inhibition of the absorption of fatty acids but reducing their release into the blood via typical routes. Practical significance of this mechanism to oral supplementation is not yet known

In rats subject to a controlled diet containing 0.375% TTA over the course of 50 weeks, there appears to be a modification in the fatty acids of cardiac tissue with a decrease in saturated fat and arachidonic acid content with an increase in fish oil fatty acids, and this effect was additive with fish oil supplementation (10.4% of diet).^[10]

May increase fish oil fatty acid content of the heart independent of fish oil supplementation

The scavenger receptor A (SRA) is a receptor that is thought to play antiinflammatory (via reducing TNF-α^[11]) and antiatherosclerotic roles (by reducing LDL cholesterol levels^[12]).

One study in humans with HIV given TTA supplementation for one month at the dose of 1,000mg found that supplementation was associated with an increase in scavenger receptor A (SRA) with supplementation without any influence on LDL receptor mRNA (in tested PMBCs).^[13] The authors noted that, in mice, supplementation caused an increase in hepatic SRA mRNA content within five days of supplementation although these mice also experienced increases in LDL receptor mRNA in the liver^[13] and due to an inverse relation between total cholesterol levels and TNF-α concentrations it was thought that the SRA played a significant role.

In addition to the above mechanisms (reduction of fatty acids in the blood, reduced fat mass) TTA can alleviate the decrease in insulin sensitivity from a fat promoting diet.^[14] and has antioxidant abilities.^[15] Thus TTA may be a potent cardioprotective agent, and appears to be more protective in the metabolically impaired.^[16]

In non-metabolically impaired hearts, TTA may suppress overall cardiac output via the increase in fatty acid oxidation causing a decrease in glucose oxidation.^[17]

A study in persons with HIV on anti-viral therapy who were then given 1,000mg of TTA supplementation daily over the course of one month failed to find any modifications in HbA1c concentrations relative to baseline.^[13]

In persons with HIV on antiviral therapy given an additional 1,000mg TTA, supplementation failed to significantly alter insulin sensitivity relative to baseline.^[13]

When supplemented to an obesity-inducing and insulin resistance promoting diet, TTA shows promise in negating a fair bit of the gain in mass and completely ameliorating the onset of peripheral insulin resistance.^[18] It seems to do this effect via increasing uptake of fats from the blood into tissues that express PPARa (muscle and liver mostly, some kidney) and then to oxidize the fats.^[18][19] With superloading of TTA (at 200mg/kg bodyweight) rats experienced weight loss despite eating a greater amount of calories.^[20]

No significant effects of TTA at 1g daily over 28 days in dyslipidemic diabetic men has been noted where weight remained stable at 96.3+/-15.9kg,^[1] and supplementation of the same dose of TTA for 28 days in HIV positive (normal weight) persons on a controlled diet (to reduce blood lipids and maintain weight) has failed to significantly reduce body weight relative to baseline.^[13]

One study investigating the influence of TTA on persons with HIV currently undergoing anti-viral therapy found a decrease of the circulating inflammatory cytokine TNF-α yet no influence on viral loads in immune cells.^[13]

The lone study of TTA in persons with HIV noted that it was safe to use, but failed to find any modification (beneficial or negative) to the viral loads in these subjects

One study assessing the safety and pharmacology of supplemental TTA noted that one subject in the 1,000mg group experienced an increase in free T4 and reduction in TSH, although it was not deemed clinically relevant and over the whole group there were no other noticeable changes in thyroid function.^[4]

TTA appears to induce mitochondrial β-oxidation in liver cells (mice) via activation of PPARα^[21] and in cultured cells treated with TTA a decrease in triglycerides is noted;^[6] this is thought to underlie both antiobese and lipid lowering properties of TTA.^[22] Beyond activation of PPARα, PPARδ^[1] may also be a target as are the stress factors mTOR and ERK1/2.^[23]

Increasing fatty acid oxidation in the liver may underlie some antiobese and lipid lowering properties of supplemental TTA

Oral supplementation of TTA in both rats^[24] and humans (at 1,000mg daily for four weeks^[3]) has been noted to increase the amount of oleic acid (an omega-9 fatty acid found in many foods such as olive oil) in the body relative to other fatty acids despite a downward trend of overall fatty acid content in the blood. This is thought to be due to the delta 9 desaturase (Δ9D) enzyme which produces oleic acid from saturated fatty acids in the body^[25] being increased (independent of possible PPARα activation from TTA^[25]) as TTA itself is thought to be primarily metabolized by this enzyme.

Possibly related to how TTA is metabolized by the delta-9-desaturase enzyme, this enzyme's activity may be increased which is thought to result in a higher rate of production of oleic acid from other fatty acids in the body. The end result being a higher relative content of oleic acid.

TTA supplementation can also alleviate damages to the kidneys and prevent subseqeunt increases in blood pressure.^[24][26]

In otherwise healthy humans given TTA for a period of a week at 1,000mg no noticeable damage occurred to the kidneys as assessed by their biomarkers in the blood.^[4]

Psoriasis is an inflammatory skin disease which is characterized by an increase in the inflammatory response and its cytokines (mediators of inflammation in the body) such as TNF-α^[27] resulting in an inflammatory response in the skin characterized by redness, thickness, and scaleness of the skin.^[28] Due to the previously noted ability of Tetradecyl thioacetic acid (TTA) to reduce the aforemetnioned cytokine following oral administration^[13] it has been investigated for the treatment of psoriasis.

A topical cream containing 0.5% tetradecyl thioacetic acid (TTA) given to psoriatic patients failed to exert any anti-psoriatic effects in a small pilot study^[29] whereas elsewhere in a larger trial oral supplementation of 1,000mg TTA over the course of four weeks showed a reduction in inflammatory biomarkers in persons with psoriasis (ICAM-1, IL-8, TNF-α) but psoriasis symptoms were not directly assessed.^[3]

While TTA may possess an anti-inflammatory effect, there is currently no evidence to demonstrate an ability of TTA to actively treat psoriasis. The body of evidence for this, however, is limited

28 days supplementation of TTA was able to significantly reduce circulating Vitamin E levels by about 2nM, which was said to be due to the tight relationship with serum Vitamin E and serum lipids.^[1] TTA is able to slightly reduce total circulating lipids in both healthy persons^[4] and moreso in those with metabolic ailment (diabetes) due to higher baseline lipids,^[1] supporting this hypothesis. The reduction in serum Vitamin E, while statistically significant, does not appear to be large enough to be clinically worrisome.^[1]

Due to reducing overall lipids in the blood, it is possible that TTA can reduce things that bind to lipids to transport themselves around the body. This has been demonstrated with Vitamin E and should apply to other fat soluble nutrients (CoQ10 and carotenoids) although it does not seem to be enough of a reduction to be clinically worrisome.

The two main fatty acids in fish oil, EPA and DHA, had their circulating levels decreased by 10% and 13% respectively, after 28 days of 1g TTA supplementation in diabetic and hyperlipidemic men,^[1] which the authors attributed to increase peroxisomal fatty acid oxidation favoring omega-3 polyunsaturated fatty acids, which is seen in rats.^[30]

Tetradecyl thioacetic acid (TTA) has been subject to toxicity testing based on the concern that, secondary to its fat solubility, it could be stored in the body for prolonged periods of time and have chronic effects different from acute effects. Preliminary investigation into human consumption have found no adverse effects at doses of 300-1000mg a day for 7 consecutive days in otherwise healthy adult men^[4] while another study noted no side effects at 1000mg for 28 days in diabetic males.^[1]

Unpublished preclinical toxicity studies in dogs and rats (unpublished, but mentioned in citation) have apparently concluded little to no risk of toxicity.^[1]

No apparent toxicity at this moment in time with oral doses up to 1,000mg daily for a period of up to one month, with no data of either higher doses or longer periods of time in humans