IngredientsThe synthetic saturated fatty acid tetradecylthioacetic acid (TTA) is comprised of a 16-carbon backbone with an insertion of a sulfur atom in position 3 (Ī²-position) from its carboxyl end. This gives it the chemical structure of palmitic acid (C16) in which a sulfur atom is located between the 2 and 3-carbon atoms, expressed as COOH-CHā-S-(CHā)āā-CHā.
TTA carries the molecular formula CāāHāāOāS and a molecular weight of 288.5 g/mol. Its CAS registry number is 2921-20-2. According to ChEBI, 2-(tetradecylthio)acetic acid is classified as a straight-chain fatty acid.
Synonyms used in the scientific and chemical literature include 1-(carboxymethylthio)tetradecane, acetic acid 2-(tetradecylthio)-, and 2-(tetradecylthio)acetic acid, with the abbreviation TTA being the most widely used identifier. DrugBank has assigned it accession number DB18802 and categorizes it as an investigational small molecule.
Physical properties include a melting point of 65ā73 Ā°C and a predicted boiling point of approximately 402.6 Ā°C, with a density of approximately 0.957 g/cmĀ³.
The sulfur atom is more electronegative than carbon; accordingly, the 3-thia acid is slightly more acidic than its corresponding fatty acid, and thia fatty acids are also more polar and slightly more soluble in water than fatty acids of corresponding chain length.
As a peroxisome proliferator-activated receptor (PPAR) pan-agonist, TTA belongs to a class of 3-thia fatty acids, which are non-Ī²-oxidizable analogs designed to mimic natural fatty acids but resist metabolic breakdown at the Ī²-position due to the sulfur substitution.
Tetradecylthioacetic acid (TTA) is a synthetic fatty acid used as a nutritional supplement. It does not occur naturally in foods or botanical sources. TTA is synthesized chemically, classically from 1-bromotetradecane and thioglycolic acid. Its development arose from research into structurally modified fatty acids intended to study and manipulate lipid metabolism, particularly in the context of peroxisome biology.
During the last two decades, chemically modified fatty acid (FA) analogs have been produced in an attempt to achieve FAs having increased metabolic stability and more selective and targeted effects. Among these is the bioactive, saturated 3-thia FA tetradecylthioacetic acid (TTA). The compound has been extensively developed and studied by researchers at the University of Bergen, Norway, most prominently by Rolf K. Berge and colleagues.
TTA has no traditional or ethnobotanical history of use. It is an entirely synthetic compound first described in the scientific literature in the late 1980s and early 1990s as part of systematic research into thia fatty acid biochemistry. There are no recorded uses in folk medicine, Ayurveda, traditional Chinese medicine, or any other historical healing system. All documented research is modern and laboratory-based.
The PPAR-activating properties of TTA were first identified in the early 1990s through studies linking it to peroxisome proliferation in hepatocytes. Research by Berge and colleagues demonstrated that TTA, a non-Ī²-oxidizable sulfur-substituted fatty acid analog, strongly activated PPAR in rat liver cells, inducing peroxisomal enzyme activities to levels comparable to known proliferators. This seminal work established TTA's role in PPAR-mediated pathways, paving the way for subsequent mechanistic investigations.
TTA is itself the sole active entity. It is not a plant extract or complex mixture. Its biological activity arises entirely from its unique structural configuration: a long-chain fatty acid backbone in which a sulfur atom replaces a methylene group at the Ī²-carbon. Because TTA is a pure synthetic compound, discussion of "constituents" necessarily concerns its metabolites and structural analogs.
Tetradecylthioacetic acid (TTA), a synthetic 3-thia fatty acid analog, is non-metabolizable via classical routes due to sulfur substitution at the beta-position (C3), which prevents its own degradation via mitochondrial beta-oxidation by inhibiting the initial dehydrogenation step catalyzed by acyl-CoA dehydrogenases. This thioether linkage specifically blocks the subsequent hydration by enoyl-CoA hydratase, halting the pathway and allowing TTA to persist intracellularly as a stable ligand.
The relatively slow hepatic and renal occurring metabolism of TTA instead involves Ļ-oxidation followed by partial Ī²-oxidation from the omega end. Although TTA has physicochemical properties similar to natural fatty acids, it can act as a substrate for desaturation and incorporation into glycerolipids, preferably into the phospholipid fraction.
In the Phase I human study, TTA did not induce significant changes in blood lipids or free fatty acids, but it did result in an increase in plasma concentration of Ī9 desaturated TTA (TTA: 1n-8). This desaturated metabolite represents the primary identified circulating derivative.
TTA has been shown to be a potent ligand for nuclear receptors of the peroxisome proliferator-activated receptor (PPAR)-family. All three rodent peroxisome proliferator-activated receptor (PPAR) subtypes are activated by TTA in the ranking order PPARĪ± > PPARĪ“ > PPARĪ³.
This modification renders TTA unable to undergo complete Ī²-oxidation and increases its biological activity, including activation of peroxisome proliferator-activated receptors (PPARs) with preference for PPARĪ±. In addition, some hypolipidemic effects of TTA have been demonstrated to be partly PPARĪ± independent, thus supporting the hypothesis that TTA acts as a PPAR pan-ligand activating also PPARĪ³ and Ī“.
Expression of PPARĪ³ target genes in adipose tissue was unaffected by TTA treatment, whereas the hepatic expression of PPARĪ±-responsive genes encoding enzymes involved in fatty acid uptake, transport, and oxidation was induced.
Tetradecylthioacetic acid (TTA) is a fatty acid analogue lacking the ability to undergo mitochondrial Ī²-oxidation. TTA promotes hepatic proliferation of mitochondria and peroxisomes and also decreases serum triglycerides and cholesterol in animals.
The biological responses to tetradecylthioacetic acid include mitochondrial proliferation, increased catabolism of fatty acids, antiadiposity, improvement in insulin sensitivity, antioxidant properties, reduced proliferation and induction of apoptosis in rapidly proliferating cells, cell differentiation, and anti-inflammatory action.
TTA is a hypolipidemic antioxidant with immunomodulating properties involving activation of peroxisome proliferator-activated receptors (PPARs).
Key mechanistic findings include: TTA suppressed the tumor necrosis factor Ī±āinduced expression of vascular cell adhesion molecule 1 (VCAM-1) and interleukin 8 (IL-8) in human endothelial cells (HUVECs). No TTA-mediated attenuation of VCAM-1 and chemokine expression was seen in the liver of PPARĪ±-knockout mice. Whereas TTA markedly enhanced PPARĪ± target genes in the liver of wild-type but not PPARĪ±ā/ā mice, no such effect on PPARĪ± target genes was seen in HUVECs. This dual pathway ā both receptor-dependent and receptor-independent ā is considered a defining characteristic of TTA's anti-inflammatory activity.
ANG II promotes inflammation through nuclear factor-kappa B (NF-ĪŗB)-mediated induction of cytokines and reactive oxygen species (ROS). TTA, as a modified fatty acid, has been studied for its effects on NF-ĪŗB, proinflammatory markers, ROS, and nitric oxide (NO) production.
TTA cannot be beta-oxidized and its treatment induced apoptosis in IPC-81 leukemia cells via depolarization of the mitochondrial membrane potential (ĪĪØ) and early release of cytochrome c, accompanied by depletion of mitochondrial glutathione. TTA seems to trigger apoptosis through mitochondrial-mediated mechanisms and selective modulation of the mitochondrial redox equilibrium.
The hypolipidemic effect of tetradecylthioacetic acid is sustained after prolonged administration and may, at least in part, be due to increased fatty acid oxidation and upregulated LDL-receptor gene expression. The increase in lipogenic enzyme activities as well as increased 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity may be compensatory mechanisms to maintain cellular integrity.
TTA is a novel hypolipidemic compound which has been shown to combine several effects of Ļ-3 polyunsaturated fatty acids, such as EPA, and structurally unrelated peroxisome proliferators, such as phenylacetate and fibrates.
In mice receiving a high-fat diet (HFD) supplemented with 0.75% (w/w) TTA, animals had significantly lower body weights compared to mice fed the diet without TTA; plasma triacylglycerol (TAG) was reduced 3-fold with TTA treatment, concurrent with an increase in liver TAG; total cholesterol was unchanged in plasma and liver; however, TTA promoted a shift in the plasma lipoprotein fractions with an increase in larger HDL particles.
Resembling other PPARĪ± agonists, TTA administration to rodents has a pronounced plasma triacylglycerol reducing effect. Histological analysis of the small intestine revealed a reduced size of lipid droplets in enterocytes of TTA-treated mice, accompanied by increased mRNA expression of fatty acid transporter genes.
Compared to liver, a large amount of TTA accumulated in the heart, and this accumulation was accompanied by an increase in omega-3 fatty acids, particularly 22:6(n-3) and a decrease in omega-6 fatty acids, mainly 20:4(n-6).
An exploratory study of safety and effects of TTA was conducted in patients with type 2 diabetes mellitus, with investigation of the mechanism of action also performed in human cell lines. Sixteen male patients with type 2 diabetes mellitus received 1 g TTA daily for 28 days in an open-labelled study, with measurement of parameters of lipid metabolism, glucose metabolism, and safety (ClinicalTrials.gov NCT00605787). The mechanism of action was further investigated in a human liver cell line (HepG2) and in cultured human skeletal muscle cells (myotubes).
Results showed that mean LDL cholesterol level declined from 4.2 to 3.7 mmol/L (p < 0.001), accompanied by increased levels of the HDL apolipoproteins A1 and A2, and a decline in LDL/HDL ratio from 4.00 to 3.66 (p = 0.008). These results demonstrated for the first time that TTA attenuates dyslipidaemia in patients with type 2 diabetes mellitus, with effects potentially occurring through mechanisms involving PPAR-alpha and PPAR-delta activation, resulting in increased mitochondrial fatty acid oxidation.
Limitations: This was a small (n=16), open-label, uncontrolled exploratory study in a single sex (male), with no placebo comparison. Findings are preliminary and cannot establish causation independently.
Highly active antiretroviral therapy (HAART) often leads to a dramatic improvement in clinical, viral and immunologic parameters in HIV-infected individuals. However, the emergence of long-term side-effects of HAART, and in particular dyslipidaemia, is increasingly reported.
Ten HIV-infected patients on protease inhibitor-based HAART with hyperlipidaemia followed a cholesterol-lowering diet throughout the study period (8 weeks). During the last 4 weeks of the study all patients received TTA (1 g once daily) in addition to the cholesterol-lowering diet. TTA in combination with dietary intervention significantly reduced total cholesterol, LDL, triglycerides, and LDL/HDL ratio in these patients, while also lowering plasma TNF-Ī± levels ā suggesting both lipid-lowering and anti-inflammatory effects potentially mediated by upregulation of scavenger and LDL receptors.
The authors concluded that, although few patients were studied, the pilot study suggests that TTA combined with dietary intervention could be an interesting therapeutic approach in HIV-infected patients on HAART, potentially resulting in both hypolipidaemic and anti-inflammatory effects.
Limitations: This was an uncontrolled pilot study with n=10, using TTA in combination with dietary modification, making it impossible to isolate the contribution of TTA alone. Evidence strength is very low.
The Phase I study described the clinical, hematological, and biochemical safety of TTA. A total of 18 healthy volunteers were included and randomly assigned into 3 groups according to the daily given dose: group 1 (200 mg), group 2 (600 mg), and group 3 (1000 mg). TTA was given as a single oral dose for 7 consecutive days.
Few adverse events of mild severity were reported. No clinically significant changes were observed in the hematological or clinical chemical parameters in blood/urine. TTA did not induce significant changes in the blood lipids or free fatty acids, but it did result in an increase in plasma concentration of Ī9 desaturated TTA (TTA: 1n-8).
Clinical verdict on lipid effects: In human clinical study there have been mixed observations in preliminary studies. One Phase I study showed no significant changes in the blood lipids or free fatty acids, and another showed that TTA attenuates dyslipidemia in patients with type 2 diabetes mellitus. Overall, evidence on lipid outcomes in humans remains preliminary and inconsistent across study populations.
TTA's ability to prevent diet-induced and genetically determined adiposity and insulin resistance has been evaluated in rodents. In Wistar rats fed a high-fat diet, TTA administration completely prevented diet-induced insulin resistance and adiposity. In genetically obese Zucker (fa/fa) rats, TTA treatment reduced the epididymal adipose tissue mass and improved insulin sensitivity.
The effects on feed intake and body weight during 7 weeks of dietary supplementation with TTA (approximately 200 mg/kg bw) were studied in male Wistar rats fed a lard-based diet containing approximately 40% energy from fat. Adipose tissue mass, body composition, and expression of relevant genes in fat depots and liver were measured. Despite higher feed intake during the final 2 weeks of the study, rats fed on TTA gained less body weight than lard-fed rats and had markedly decreased subcutaneous, epididymal, perirenal and mesenteric adipose depots.
Human evidence: No dedicated controlled human clinical trials on body weight or insulin resistance as primary endpoints have been published as of the current literature. Evidence is limited to animal models and is not directly translatable to humans.
TTA is a moderate pan-activator of peroxisome proliferator-activated receptors (PPARs), and has in previous studies shown potential as an antioxidant and anti-inflammatory agent, both through PPAR and non-PPAR mediated mechanisms.
TNF-Ī±, IL-1Ī², and IL-6 were reduced at the protein and mRNA level in TTA-treated rats. Moreover, TTA-treated rats demonstrated reduced colonic oxidative damage, while inducible nitric oxide synthase 2 mRNA expression was elevated in both the dextran sulfate sodium (DSS)- and TTA+DSS-groups. PPARĪ³ signaling may be involved in the anti-inflammatory response to TTA, as Pparg mRNA expression was significantly upregulated in colon. This study demonstrated that the pan-PPAR agonist TTA reduced colonic oxidative damage and cytokine levels in a rat model of colitis.
In a rat model of two-kidney, one-clip (2K1C) hypertension, the 2K1C TTA-treated group had lower blood pressure (128 Ā± 3 mmHg) compared with the 2K1C nontreated group (178 Ā± 5 mmHg, P < 0.001).
Atlantic salmon experiments have shown that TTA-supplemented diets significantly reduce mortality during natural outbreaks of viral diseases, suggesting a modulatory role of the immune system.
TTA exerts both hypolipidemic and anti-inflammatory effects in psoriasis patients, and TTA can be of therapeutic benefit for a subgroup of psoriatic patients. A pilot study (Morken et al., 2011, Scand J Clin Lab Invest) examined the anti-inflammatory and hypolipidemic effects of TTA (1000 mg daily for 28 days) in psoriasis patients. This work showed that TTA attenuates tumor necrosis factor-Ī±āmediated endothelial cell activation, supporting anti-inflammatory effects of this fatty acid; the relevance of these findings to human disease was suggested by a TTA-mediated downregulation of inflammatory mediators in psoriasis patients.
Limitations: The psoriasis study was a small pilot study with no placebo control. Evidence is preliminary and insufficient to draw firm therapeutic conclusions.
TTA was investigated in a rat model of post-myocardial infarction heart failure. TTA had a beneficial effect on cardiac function in post-myocardial infarction heart failure without affecting myocardial remodeling. These effects of TTA on myocardial function were accompanied by decreased free fatty acids in plasma, increased myocardial proportion of n-3 polyunsaturated fatty acids (PUFA) and a decreased proportion of n-6 PUFA.
This study suggests that TTA may improve myocardial function in heart failure, potentially involving its ability to decrease the availability of free fatty acids and increase the myocardial proportion of n-3 PUFA.
These biological responses indicate that tetradecylthioacetic acid changes the plasma profile from atherogenic to cardioprotective.
Decreased levels of 20:4(n-6) combined with increased omega-3/omega-6 ratio in cardiac tissue after TTA treatment may have influence on membrane dynamics and function.
Research has additionally explored TTA's effects on coronary restenosis. A study published in Atherosclerosis (Kuiper et al., 2001) demonstrated that TTA reduces stenosis development after balloon angioplasty injury of rabbit iliac arteries. Local delivery studies in porcine coronary arteries showed sustained retention of TTA after local administration.
Human evidence: No randomized controlled trials of TTA for cardiovascular disease endpoints in humans have been published. Evidence is confined to preclinical animal models.
TTA has been found to inhibit growth of glioma, leukemia, and colon cancer cell lines in vitro and in vivo, and hepatoma and breast cancer cells in vitro.
Glioma: In cell culture experiments, the PPARĪ³-selective ligand BRL49653 moderately inhibited growth of rat BT4Cn glioma cells, whereas administration of TTA resulted in a marked growth inhibition. Administration of the PPARĪ³-selective antagonist GW9662 abolished BRL49653-induced growth inhibition, but only marginally reduced the effect of TTA. TTA reduced tumor growth and increased the survival time of rats with implanted BT4Cn tumor. TTA-induced apoptosis in BT4Cn cells, and the administration of TTA led to cytochrome c release from mitochondria and increased the glutathione content in glioma cells. The results indicate that TTA inhibits proliferation of glioma cancer cells through both PPARĪ³-dependent and PPARĪ³-independent pathways, of which the latter appears to predominate.
Leukemia: The sulfur-substituted fatty acid TTA inhibits proliferation and induces apoptosis in lymphoma and leukemic cell lines. In an animal model, rats were transplanted with either acute promyelocytic leukemia or acute T-cell leukemia and randomized to isoenergetic diets containing either lard (control), Ļ3 (n-3) PUFA, or TTA. Whereas TTA prolonged survival (P < 0.05) in both types of rat leukemia, n-3 PUFA had no significant effect compared to controls. Only TTA inhibited (P < 0.05) leukemic infiltration in the bone marrow and spleen, probably due to apoptosis of the leukemic cells. Plasma metalloproteinase activity, a marker of metastatic activity, was significantly reduced in TTA-fed rats only.
Colon Cancer: TTA reduced SW620 human colon cancer cell growth, measured as baseline cell index, by 35% and 55% after 48 h and 72 h, respectively. TTA-induced growth inhibition of SW620 cells seems to be mediated through induction of ER stress and activation of the unfolded protein response (UPR) pathway.
Evidence strength: All oncological evidence for TTA is preclinical, consisting of cell culture and rodent experiments. No human clinical trials on TTA as an anticancer agent have been published. The mechanisms identified ā including mitochondrial apoptosis, ER stress induction, and PPAR-dependent growth inhibition ā are biologically plausible but require human investigation before any clinical significance can be established.
The effect of TTA on NF-ĪŗB, proinflammatory markers, ROS, and nitric oxide production was examined in two-kidney, one-clip (2K1C) hypertension in rats. The 2K1C TTA-treated group had significantly lower blood pressure (128 Ā± 3 mmHg) compared to the 2K1C nontreated group (178 Ā± 5 mmHg, P < 0.001).
In hypertensive rats, TTA effectively reduced high blood pressure and prevented organ damage while improving lipid metabolism. This evidence is limited to animal models; no human studies on hypertension as a primary endpoint have been published.
TTA is formulated as an oral supplement. The following dosages appear in the peer-reviewed literature:
The highest human dose tested in a controlled study was 1000 mg/day for 7 days (Phase I) and 1000 mg/day for 28 days in the diabetes and psoriasis populations. No dose-ranging studies beyond Phase I in human subjects have been published.
Serum concentration pattern of TTA at day 1 showed a 1.5-hour lag time followed by a rapid absorption and a slower elimination phase. The median peak values were 2.9 mg/L (range, 1.1 to 5.4 mg/L), 11.5 mg/L (range, 4 to 35 mg/L), and 11 mg/L (range, 5 to 25 mg/L) in groups receiving 200 mg, 600 mg, and 1000 mg, respectively (P = 0.006).
The time to peak levels were 3.5 hours (range, 2.5 to 6.5 hours), 2.5 hours (range, 2.5 to 4.5 hours), and 4.5 hours (range, 2.5 to 12 hours), respectively, for the three dose groups (P = 0.2).
This chemical modification still allows TTA to be absorbed in the intestine and transported to the liver where it can act as substrate for desaturation and incorporation into glycerolipids, preferably into the phospholipid fraction.
The relatively slow hepatic and renal occurring metabolism of TTA involves Ļ-oxidation followed by partial Ī²-oxidation from the omega end.
Researchers have noted that poor bioavailability may limit the clinical effectiveness of TTA at standard oral doses. Given that the apparent clinical benefits of TTA administration were offset by dose limitation and poor bioavailability, structural modifications such as esterification and delivery systems such as liposomes have been discussed as potential strategies to improve its therapeutic potential.
In the Phase I study, TTA was determined to be safe and well tolerated. Few adverse events of mild severity were reported. No clinically significant changes were observed in the hematological or clinical chemical parameters in blood/urine.
The 10-thiastearic acid analog tetradecylthioacetic acid has been reported to have low toxicity in humans at up to 1 g/day.
In the safety study, 18 subjects were given daily doses of 200ā1000 mg TTA for seven consecutive days. The authors concluded that TTA at its highest dose was well tolerated by humans; however, studies of long-term effects are needed.
A preclinical safety signal of note emerged from cardiac research. A study on normal mice showed that TTA increased myocardial fatty acid (FA) oxidation, which was associated with decreased cardiac efficiency and impaired postischemic functional recovery. This finding, in healthy (non-failing) animals, represents a potential concern distinct from the beneficial effects seen in heart failure models, and underscores the context-dependence of TTA's cardiac effects.
Plasma triacylglycerol was reduced with TTA treatment, concurrent with an increase in liver TAG. This redistribution of TAG from plasma to liver has been consistently observed in animal studies and has not yet been fully characterized in human settings over longer durations.
The duration of human exposure studies is limited. The longest human treatment period published in the peer-reviewed literature is 28 days at 1 g/day. No long-term (months to years) human safety data exist in the published record. Further research is needed to confirm its therapeutic efficacy and safety.
TTA is classified by DrugBank as an investigational compound, not a licensed drug or approved dietary supplement in major regulatory jurisdictions. It does not appear on any approved monograph from the WHO, European Medicines Agency (EMA), EFSA, or German Commission E. Its use in human dietary supplements operates in a regulatory environment without formal approval for specific health claims or safety thresholds established by a regulatory body.
Health conditions that Tetradecylthioacetic acid may help support.
Body systems that Tetradecylthioacetic acid may help support.
Go back