Regulation of gene expression of three putative longchain fatty acid transport proteins, fatty acid translocase (FAT), mitochondrial aspartate aminotransferase (mAspAT), and fatty acid transport protein (FATP), by drugs that activate peroxisome proliferator-activated receptor (PPAR) ␣ and ␥ were studied using normal and obese mice and rat hepatoma cells. FAT mRNA was induced in liver and intestine of normal mice and in hepatoma cells to various extents only by PPAR␣-activating drugs. FATP mRNA was similarly induced in liver, but to a lesser extent in intestine. The induction time course in the liver was slower for FAT and FATP mRNA than that of an mRNA encoding a peroxisomal enzyme. An obligatory role of PPAR␣ in hepatic FAT and FATP induction was demonstrated, since an increase in these mRNAs was not observed in PPAR␣-null mice. Levels of mAspAT mRNA were higher in liver and intestine of mice treated with peroxisome proliferators, while levels in hepatoma cells were similar regardless of treatment. In white adipose tissue of KKAy obese mice, thiazolidinedione PPAR␥ activators (pioglitazone and troglitazone) induced FAT and FATP more efficiently than the PPAR␣ activator, clofibrate. This effect was absent in brown adipose tissue. Under the same conditions, levels of mAspAT mRNA did not change significantly in these tissues. In conclusion, tissue-specific expression of FAT and FATP genes involves both PPAR␣ and -␥. Our data suggest that among the three putative long-chain fatty acid transporters, FAT and FATP appear to have physiological roles. Thus, peroxisome proliferators not only influence the metabolism of intracellular fatty acids but also cellular uptake, which is likely to be an important regulatory step in lipid homeostasis.
1 Neurotrophic factors have been used for the treatment of several neurodegenerative diseases. However, their use is limited by their inability to cross the blood-brain barrier, their short half life and their side eects. SR 57746A is a new orally active compound that exhibits in vivo and in vitro neurotrophic eects in several experimental models. 2 We show here that SR 57746A (1 mM) increases the phenotypic survival of embryonic puri®ed mouse motoneurons in vitro to the same extent as brain-derived neurotrophic factor (100 ng ml 71 ), and increases the outgrowth and number of their neurites. It acts in a dose-dependent manner up to 1 mM which is the optimal concentration. Above this concentration, its neurotrophic eect decreases. 3 Genistein (10 mM), a protein tyrosine kinase inhibitor, also increases the phenotypic survival and dierentiation of mouse motoneurons. It does not act in a synergistic or additive manner with SR 57746A. However, at concentrations equal or superior to 25 mM, it decreases the survival of motoneurons. This suggests that the neurotrophic eect of genistein is due to a favourable alteration of equilibrium between phosphorylated and dephosphorylated states of proteins involved in survival and dierentiation of motoneurons. 4 Like genistein, SR 57746A should be used at a critical concentration (1 mM) to exert its optimal eects. Since SR 57746A does not act synergistically with genistein, it is likely that its mechanism of action involves a pathway similar to that aected by this tyrosine kinase inhibitor. 5 At the present time, SR 57746A is the only orally active compound and the only synthetic compound shown to be active on motoneurons in vitro. It should thus be considered as a good candidate for the treatment of motoneuron diseases.
Key words: Peroxisome proliferator-activated receptor; Peroxisome proliferator response element; 9-cis Retinoic acid receptor alpha; Rat peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase; Transcriptional activation sists of direct repeats of the sequence TGACCT, the consensus binding sequence for several members of the nuclear steroid hormone receptor superfamily [7]. PPAR binds to these PPREs through heterodimerization with the 9-cis retinoic acid receptor RXR~ [4,8]. Transcriptional activation is regulated by diverse auxiliary transcription factors that can act as activators or repressors. For instance, the chicken ovalbumin upstream promoter-transcription factor (COUP-TF) can bind to the HD-PPRE and antagonizes peroxisome proliferators activation [9]. In fact, different studies on hormone response elements have shown that many known and unknown factors are able to bind promiscuous sequences [10][11][12]. Here we show that the PPAR-RXR heterodimer activates transcription via the DR1 part of the HD-PPRE and that other transcription factors modulate the level of induction via the most 5"-receptor motif in DR2.
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