Abstract
3-Thia fatty acids are modified fatty acids that promote hepatic peroxisome proliferation and decrease serum triacylglycerol, cholesterol and free fatty acid levels in rats. In vivo administration of tetradecylthioacetic acid (TTA) to rats led to a significant decrease in liver apolipoproteins apoA-I, A-II, A-IV, and C-III mRNA levels, and to an increase of liver acyl-CoA oxidase (ACO), carnitine palmitoyltransferase-II, and 3-hydroxy-3-methylglutaryl coenzyme A synthase (HMG-CoA synthase) mRNA levels and activities. By contrast, no significant changes of lipoprotein lipase (LPL) mRNA levels were detected in rat epididymal adipose tissue. Liver carnitine palmitoyltransferase-I, apoB, apoE, and LDL receptor mRNA levels were not significantly affected. When tested in vitro, TTA increased rat ACO and carnitine palmitoyltransferase-I mRNA levels in primary rat hepatocytes and also LPL mRNA levels in 3T3-L1 preadipocytes. TTA also enhanced the transcriptional activity of chimeras containing the DNA binding domain of the yeast transcription factor Gal4 fused to the ligand binding domain of either human PPARalpha or human PPARgamma. The effect depended on the concentration tested and the cell type. In conclusion, our data suggest that in vitro, TTA activates both PPARalpha and PPARgamma, but the latter with much lower affinity. TTA affects serum lipid levels in vivo in rats by acting mainly on the liver via PPARalpha where it decreases the liver expression of genes involved in vascular lipid transport and increases the expression of genes involved in intracellular fatty acid metabolism. -Raspé, E., L. Madsen, A-M. Lefebvre, I. Leitersdorf, L. Gelman, J. Peinado-Onsurbe, J. Dallongeville, J-C. Fruchart, R. Berge, and B. Staels. Modulation of rat liver apolipoprotein gene expression and serum lipid levels by tetradecylthioacetic acid (TTA) via PPARalpha activation.
Highlights
3-Thia fatty acids are modified fatty acids that promote hepatic peroxisome proliferation and decrease serum triacylglycerol, cholesterol and free fatty acid levels in rats
The functions of these apolipoproteins in plasma lipoprotein metabolism were unravelled by the phenotypic analysis of naturally occurring mutants or of strains of transgenic mice either overexpressing the human apolipoprotein genes or carrying mutations in endogenous apolipoprotein genes introduced by homologous recombination [11, 12]
We mainly focused the present study on apoA-I, apoC-III, and lipoprotein lipase (LPL), important participants in high density lipoprotein (HDL) and triacylglycerol metabolism
Summary
Tetradecylthioacetic acid (TTA) was prepared as described earlier [42]. BRL49653 and fenofibric acid were gifts respectively from Dr J-J. The plasmids (pG5TkpGL3 at 100 ng/well (reporter); pGal4-hPPAR␣DEF, pGal4-hPPAR␥DEF and pGal4- at 10 ng/well (expression vectors) and pRL-CMV at 1 ng/well) were dissolved in serum-free DMEM supplemented with NaCl (150 mm), sodium bicarbonate (50 mm) and the cationic lipid (6 nmol/g DNA), vortexed, incubated for 30 min at room temperature, and added to the cells. After 2 h, cells were washed with 0.15 m NaCl, 0.01 m sodium phosphate buffer, pH 7.2, and incubated for 36 h in fresh medium containing 10% fetal calf serum and the compounds tested or vehicle (DMSO 0.1% by vol). At the end of the experiment, the cells were washed once with ice-cold 0.15 m NaCl, 0.01 m sodium phosphate buffer, pH 7.2, and the luciferase activity was measured with the Dual-LuciferaseTM Reporter Assay System (Promega, Madison, WI) according to the manufacturer’s instructions. As a better fit was generally obtained with the Hill equation, this equation and the fitted parameters were used to estimate the EC50
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