Cloning of murine TReP-132, a novel transcription factor expressed in brain regions involved in behavioral and psychiatric disorders.

In recent studies that addressed the transcriptional control of steroid synthesis, a transcriptional regulating protein of 132 kDa (TReP-132) was cloned and demonstrated to regulate expression of the human P450 side chain cleavage (P450scc) gene. In the present study, we describe the cloning and characterization of the mouse orthologue of the human factor, mouse transcriptional regulating protein (mTReP-132). mTReP-132 encodes a 1216-residue protein that is 85.5% homologous to the human protein. Both factors contain characteristic motifs, namely glutamine-, proline- and acidic-rich regions. The primary structure also exhibits two zinc fingers of the C(2)H(2) subtype, suggesting that this protein has the ability to act as a DNA binding transcription factor. mTReP-132 may also be a co-regulator of nuclear receptors because of two nuclear box motifs in this protein. Northern blot analysis demonstrated the expression of two transcripts of 4.4 and 7.5 kb in several tissues, but expression was clearly highest in the brain, thymus and testis of mice. In the brain, the hybridization signal was quite localized and strong in the basal ganglia, hippocampus, piriform cortex, cerebral cortex, ventromedial nucleus of the hypothalamus, and the dorsal and superior central nuclei of the raphe. Although classical steroidogenesis pathways have yet to be firmly established in the brain, expression of both mTReP-132 and P450scc provides anatomical evidence that mTReP-132 may regulate this key steroidogenic enzyme within specific regions involved in behavioral and psychiatric disorders. Moreover, the presence of both mTReP-132 and steroidogenic factor 1 (SF-1) transcripts in the ventromedial nucleus of the hypothalamus suggests a role for mTReP-132 in brain development and function. The molecular cloning and the highly specific expression of mTReP-132 across the brain further consolidate the hypothesis that this tissue is able to synthesize de novo steroids in a region-specific manner.

Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors activated by fatty acids and derivatives. Although PPARalpha mediates the hypolipidemic action of fibrates, PPARgamma is the receptor for the antidiabetic glitazones. PPARalpha is highly expressed in tissues such as liver, muscle, kidney, and heart, where it stimulates the beta-oxidative degradation of fatty acids. PPARgamma is predominantly expressed in adipose tissues, where it promotes adipocyte differentiation and lipid storage. PPARbeta/delta is expressed in a wide range of tissues, and recent findings indicate a role for this receptor in the control of adipogenesis. Pharmacological and gene-targeting studies have demonstrated a physiological role for PPARs in lipid and lipoprotein metabolism. PPARalpha controls plasma lipid transport by acting on triglyceride and fatty acid metabolism and by modulating bile acid synthesis and catabolism in the liver. All 3 PPARs regulate macrophage cholesterol homeostasis. By enhancing cholesterol efflux, they stimulate the critical steps of the reverse cholesterol transport pathway. As such, PPARs control plasma levels of cholesterol and triglycerides, which constitute major risk factors for coronary heart disease. Furthermore, PPARalpha and PPARgamma regulate the expression of key proteins involved in all stages of atherogenesis, such as monocyte and lymphocyte recruitment to the arterial wall, foam cell formation, vascular inflammation, and thrombosis. Thus, by regulating gene transcription, PPARs modulate the onset and evolution of metabolic disorders predisposing to atherosclerosis and exert direct antiatherogenic actions at the level of the vascular wall.