Regulation of the Liver Fatty Acid-Binding Protein Gene by Thyroid Hormone and Clofibric Acid
A Iwen, JM Weitzel & HJ Seitz
Liver fatty acid-binding protein (LFABP) is a 14 kDa cytoplasmatic protein found in hepatocytes and enterocytes of the small intestine. It binds long chain fatty acids (LCFA) and other hydrophobic ligands and is thought to play an important role in intracellular LCFA transport.
We investigated the regulation of LFABP gene expression by thyroid hormone (T3) and peroxisome proliferator-activated receptor alpha (PPARalpha) ligand clofibric acid.
First we monitored changes of LFABP mRNA concentration in vivo. T3 was intraperitoneally administered to hypothyroid Wistar rats and liver mRNAs were isolated after 0h, 6h, 24h and 48h. The rats were decapitated without anaesthesia. Northern blot analysis revealed an initial increase of LFABP mRNA concentrations after 6h and a further rise after 48h, suggesting two different mechanisms of T3 action.
To investigate the molecular basis of these effects we used a 621 bp fragment of the rat LFABP promoter in transient transfection assays. We were not able to detect a significant T3 effect. A 1722 bp human LFABP promoter fragment was also used in transient transfection assays. The T3 effect was not reproduced as well. These findings indicate, that the regulation is not exerted through T3 response elements in the promoters.
We and other researchers analyzed effects of PPARalpha ligands on LFABP gene expression. A positive regulation was shown in transient transfection assays after stimulation with clofibric acid and linoleic acid.
It is known, that free fatty acids concentrations are elevated under stress (eg intraperitoneally injection of T3) and in hyperthyroid state, thus providing a possible explanation for the in vivo findings.