Tetradecylthioacetic Acid (TTA)

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In vivo administration of tetradecylthioacetic acid (TTA) in mice causes cardiac inefficiency and reduced post-ischemic ventricular function

Anne D. Hafstad1, Ahmed M. Khalid1, Ole-Jakob How, Rolf Berge2, Terje S. Larsen1 and Ellen Aasum1

1Institute of Medical Biology, University of Troms#248;, Norway

2Institute of Medicine, University of Bergen, Norway

Available online 23 March 2007.

Myocardial fatty acid (FA) oxidation is regulated acutely by the FA supply and chronically by changes at the gene transcriptional level via the PPAR family. The aim of the present study was to examine the effects of tetradecylthioacetic acid (TTA, a pan PPAR agonist) on myocardial metabolism and ventricular function. Balb/c mice were treated for 8 days with TTA (0.5%, added to the diet).

Using the isolated working heart we examined myocardial FA and glucose oxidation, cardiac efficiency, i.e. the relationship between myocardial work (pressure?volume area, PVA) and myocardial oxygen consumption (MVO2), as well as functional recovery following 40 min low-flow ischemia.

In contrast to previous reports showing only minor changes in cardiac metabolism following PPAR treatment of normal mice, TTA treatment caused a 2.4 fold increase in myocardial FA oxidation with a concomitant reduction in glucose oxidation. Hearts from TTA-treated mice showed a marked reduction in cardiac efficiency, due to a near two-fold increase in the oxygen used for non-contractile processes (i.e. unloaded MVO2). These hearts also showed decreased recovery of ventricular function following low-flow ischemia. We conclude that TTA have a direct and strong stimulatory effect on FA oxidation in the normal mouse heart. This elevation of myocardial FA oxidation leads to a marked increase in MVO2 which could contribute to the reduced ischemic tolerance.

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Tetradecylthioacetic acid reduces the amount of lipid droplets, induces megamitochondria formation and increases the fatty acid oxidation in rat heart

Sofie Hexeberg 1, Corresponding Author Contact Information, Livar Fr#248;yland 2, Daniel K. Asiedu 2, Abraham Demoz 2 and Rolf K. Berge 2

1 Department of Anatomy and Cell Biology, University of Bergen, Norway

2 Department of Clinical Biology, Division of Biochemistry, University of Bergen, Norway

Received 23 May 1994;
accepted 1 February 1995.
Available online 23 February 2004.

Abstract

The effects of prolonged administration (3 months) of a 3-thia fatty acid analogue and omega-3-fatty acids on cardiac fatty acid oxidation and the volume fraction of lipid droplets and mitochondria in cardiomyocytes were investigated. Doses were 1 g/day/kg body weight, except 150 mg/day/kg body weight for tetradecylthioacetic acid (a 3-thia fatty acid). One group served as control and did not receive any treatment. The volume fraction of lipid droplets in cardiomyocytes was significantly lower in the tetradecylthioacetic acid group compared to the other groups. Mitochondrial β-oxidation was 60% greater and fatty acyl-CoA oxidase activity was increased by 430% in the tetradecylthioacetic acid group compared to control. This was accompanied by a greater volume fraction of mitochondria in cardiomyocytes (0.514±0.032% in tetradecylthioacetic acid v 0.318±0.007% in control) which was due to an increased size of mitochondria. The volume fraction of mitochondria was also greater in eicosapentaenoic acid (EPA) treated rats compared to control, but the enzymic activities were unaffected. Docosahexaenoic acid (DHA) treatment resulted in a greater volume fraction of lipid droplets in the cardiomyocytes, but the volume fraction of mitochondria and enzymic activities were unaltered. These results indicate that EPA and DHA have different effects on the modulation of mitochondrial biogenesis. Tetradecylthioacetic acid treatment results in megamitochondria formation and increased peroxisomal and mitochondrial β-oxidation with a concomitant reduction of lipid droplets in the cardiomyocytes.

Author Keywords: Author Keywords: 3-Thia fatty acid; Omega-3-fatty acids; Cardiomyocytes; Morphometry; Lipid droplets; Mito chondria; Mitochondrial β-oxidation; Fatty acyl-CoA oxidase

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Pharmacology and safety of tetradecylthioacetic acid (TTA): phase-1 study.

Full Abstract

This study describes the clinical, hematological, and biochemical safety of tetradecylthioacetic acid (TTA). A total of 18 healthy volunteers were included. Subjects were randomly assigned into 3 groups according to the daily given dose of

TTA:
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. Safety was evaluated by following the adverse events, vital signs, and hematological and biochemical parameters in blood and urine samples. Efficacy was estimated through its effects on plasma lipids profile. 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 Delta9 desaturated TTA (TTA:
1n-8). 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 1, 2, and 3, 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 (P = 0.2). TTA is safe and well tolerated.

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Tetradecylthioacetic acid attenuates dyslipidaemia in male patients with type 2 diabetes mellitus, possibly by dual PPAR-alpha/delta activation and increased mitochondrial fatty acid oxidation.

L#248;v#229;s K, R#248;st TH, Skorve J, Ulvik RJ, Gudbrandsen OA, Bohov P, Wensaas AJ, Rustan AC, Berge RK, Husebye ES.

Institute of Medicine, University of Bergen, Bergen, Norway. kristian.lovas@helse-bergen.no

AIM: We previously demonstrated that a modified fatty acid, tetradecylthioacetic acid (TTA), improves transport and utilization of lipids and increases mitochondrial fatty acid oxidation in animal and cell studies. We conducted an exploratory study of safety and effects of this novel drug in patients with type 2 diabetes mellitus and investigated the mechanism of action in human cell lines. METHODS: 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: 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). Total fatty acid levels declined, especially the fraction of the polyunsaturated n-3 fatty acids docosahexaenoic acid (-13%, p = 0.002) and eicosapentaenoic acid (-10%, p = 0.07). Glucose metabolism was not altered and the drug was well tolerated. In cultured liver cells, TTA acted as a pan-PPAR agonist with predominant PPAR-alpha and PPAR-delta activation at low TTA concentrations. In myotubes, TTA and a PPAR-delta agonist, but not the PPAR-alpha or PPAR-gamma agonists, increased the fatty acid oxidation. CONCLUSIONS: We demonstrate for the first time that TTA attenuates dyslipidaemia in patients with type 2 diabetes mellitus. These effects may occur through mechanisms involving PPAR-alpha and PPAR-delta activation, resulting in increased mitochondrial fatty acid oxidation.

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Pharmacology and safety of tetradecylthioacetic acid (TTA): phase-1 study.

This study describes the clinical, hematological, and biochemical safety of tetradecylthioacetic acid (TTA). A total of 18 healthy volunteers were included. Subjects were randomly assigned into 3 groups according to the daily given dose of TTA: 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. Safety was evaluated by following the adverse events, vital signs, and hematological and biochemical parameters in blood and urine samples. Efficacy was estimated through its effects on plasma lipids profile. 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 Delta9 desaturated TTA (TTA: 1n-8). 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 1, 2, and 3, 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 (P = 0.2). TTA is safe and well tolerated.

Pettersen RJ, Salem M, Skorve J, Ulvik RJ, Berge RK, and Nordrehaug JE
Journal of cardiovascular pharmacology 51(4):410-7, 2008 Apr

[BALOTSAS]

να ειχαμε και καμια μεταφραση καλα θα ηταν

[Andrikos]

εν ολίγοις το ΤΤΑ αυξάνει την καύση λίπους?

Πρώτη φορά το συναντώ στη βιβλιογραφία , νομίζω ότι πρέπει να περιμένουμε πολλές άλλες έρευνες να δούμε τι κάνει αυτή η ένωση