Modulation of rat liver apolipoprotein gene expression and serum lipid levels by tetradecylthioacetic acid (TTA) via PPAR alpha activation

3-Thia fatty acids are modified fatty acids that promote hepatic peroxisome proliferation and decrease serum triacylglycerol, cholesterol and free fat ty acid levels in rats. In vivo administration of tetradecylthioacetic acid (TTA) to rats led to a significant decrease in liver apolipoproteins apoA- I, A-LI, A-IV, and C-III mRNA levels, and to an increase of liver acyl-CoA oxidase (ACO), carnitine palmitoyltransferase-II, and 3-hydroxy-3-methylglu taryl coenzyme A,synthase (HMG-CoA synthase) mRNA levels and activities. By contrast, no significant changes of Lipoprotein lipase (LPL) mRNA levels w ere detected in rat epididymal adipose tissue. Liver carnitine palmitoyltra nsferase-I, apoB, apoE, and LDL receptor mRNA levels were not significantly affected. When tested in vitro, TTA increased rat ACO and carnitine palmit oyltransferase-I mRNA levels in primary rat hepatocytes and also LPL mRNA l evels in 3T3-L1 preadipocytes, TTA also enhanced the transcriptional activi ty of chimeras containing the DNA binding domain of the yeast transcription factor Gal4 fused to the ligand binding domain of either human PPAR alpha or human PPAR gamma. The effect depended on the concentration tested and th e cell type. In conclusion, our data suggest that in vitro, TTA activates b oth PPAR alpha and PPAR gamma, but the latter with much lower affinity, TTA affects serum lipid levels in vivo in rats by acting mainly on the liver v ia PPAR alpha 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.